Статті в журналах: "BCL7"

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Dietrich, Nicholas, Kevin Trotter, James M. Ward, and Trevor K. Archer. "BRG1 HSA domain interactions with BCL7 proteins are critical for remodeling and gene expression." Life Science Alliance 6, no. 5 (February 17, 2023): e202201770. http://dx.doi.org/10.26508/lsa.202201770.

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The SWI/SNF complex remodels chromatin in an ATP-dependent manner through the subunits BRG1 and BRM. Chromatin remodeling alters nucleosome structure to change gene expression; however, aberrant remodeling can result in cancer. We identified BCL7 proteins as critical SWI/SNF members that drive BRG1-dependent gene expression changes. BCL7s have been implicated in B-cell lymphoma, but characterization of their functional role within the SWI/SNF complex has been limited. This study implicates their function alongside BRG1 to drive large-scale changes in gene expression. Mechanistically, the BCL7 proteins bind to the HSA domain of BRG1 and require this domain for binding to chromatin. BRG1 proteins without the HSA domain fail to interact with the BCL7 proteins and have severely reduced chromatin remodeling activity. These results link the HSA domain and the formation of a functional SWI/SNF remodeling complex through the interaction with BCL7 proteins. These data highlight the importance of correct formation of the SWI/SNF complex to drive critical biological functions, as losses of individual accessory members or protein domains can cause loss of complex function.

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Jadayel, Dalal M., Lucy R. Osborne, Lionel J. A. Coignet, Valter J. Zani, Lap-Chee Tsui, Stephen W. Scherer, and Martin J. S. Dyer. "The BCL7 gene family: deletion of BCL7B in Williams syndrome." Gene 224, no. 1-2 (December 1998): 35–44. http://dx.doi.org/10.1016/s0378-1119(98)00514-9.

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McBride, Amanda, Clare M. Adams, Ramkrishna Mitra, and Christine M. Eischen. "Bclw Overexpression Predicts Aggressive Disease in B-Cell Lymphomas." Blood 136, Supplement 1 (November 5, 2020): 29. http://dx.doi.org/10.1182/blood-2020-142545.

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B-cell lymphomas encompass a phenotypically and genetically heterogenous subgroup within hematologic malignancies. Despite this heterogeneity, the ability to evade apoptosis is a unifying feature across B-cell lymphomas, and alterations within the Bcl-2 family of apoptosis regulatory proteins is a key mechanism for this evasion. While overexpression of the anti-apoptotic Bcl-2 family member BCL2 has been widely described in multiple B-cell lymphomas, altered expression of other anti-apoptotic proteins within this family, including BCLX, MCL1, A1 and, in particular, BCLW has been under-investigated. This is highlighted by clinical trials of the BCL2 inhibitor, venetoclax, which found poor single agent activity in B-cell lymphomas that were thought to be highly BCL2-dependent. Therefore, we investigated the contributions of anti-apoptotic Bcl-2 proteins in B-cell lymphomas. Analysis of gene expression profiling datasets of patient samples of major B-cell lymphoma subtypes as compared to normal B-cells demonstrated differential overexpression of anti-apoptotic Bcl-2 proteins, with BCL2, BCLX and BCLW being significantly overexpressed in multiple B-cell lymphoma subtypes. Focusing on aggressive B-cell lymphoma subtypes, BCLW was consistently overexpressed across all major B-cell lymphoma subtypes. Notably, BCLW overexpression was maintained in high grade follicular lymphoma compared to low grade, whereas BCL2 levels decreased as grade increased. These findings indicate that BCLW overexpression is selected for in more aggressive B-cell lymphoma subtypes. BCLW overexpression in aggressive B-cell lymphoma cell lines conferred resistance to the non-specific BH3 mimetic navitoclax as well as to venetoclax. Further, analysis of diffuse large B-cell lymphoma (DLBCL) cell lines demonstrated that the combination of high BCLW/low BCL2 in GCB DLBCL and high BCLW/moderate BCL2 in non-GCB DLBCL is also associated with decreased navitoclax sensitivity, suggesting that high BCLW may confer treatment resistance. In accordance with this, analysis of patient outcomes in DLBCL demonstrates that patients exhibiting high BCLW levels with low BCL2 levels have poorer survival than those with low BCLW. Moreover, Cox regression analysis showed BCLW was an independent determinant of overall survival in DLBCL. Together, our results indicate that BCLW predicts for more aggressive disease in B-cell lymphomas and increased resistance to therapy. Disclosures Eischen: AbbVie Inc.:Research Funding.

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Kahraman, Dudu Solakoglu, Gulden Diniz, Cengiz Ceylan, Faruk Recep Ozalp, Yetkin Koca, Sumeyye Ekmekci, Duygu Ayaz, and Sevil Sayhan. "Prognostic impact of BCL2, BCL6 and MYC status in de novo diffuse large B-cell lymphoma: a regional study of 43 patients." International Journal of Research in Medical Sciences 7, no. 5 (April 26, 2019): 1720. http://dx.doi.org/10.18203/2320-6012.ijrms20191665.

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Background: Diffuse large B-cell lymphoma (DLBCL) is an aggressive non-Hodgkin lymphoma with marked biologic heterogeneity. We aimed to evaluate the status of MYC, BCL2, BCL6 in patients with DLBCL.Methods: Herein, we have investigated the prognostic relevance of MYC, BCL2 and BCL6 from 43 de novo DLBCL patients.Results: In this study, protein overexpression of BCL2 and BCL6 was encountered in 46.5% (n=20) and 27.9% (n=12) of the tumors, respectively. Rearrangements in MYC, BCL6, and BCL2 were detected in 9.3% (n=4), 25.6% (n=11), and 4.7% (n=2) of the cases, respectively. Any statistically significant difference could not be found between Bcl-2, Bcl-6 expression, C-MYC rearrangement and the survival.Conclusions: We concluded that C-MYC and BCL2 may contribute to aggressive transformation, so more mechanism-based therapy should be explored. A larger study is warranted to better understand the immunophenotypic and molecular features of DLBCL and their respective impact on patient survival.

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Sun, Guoxian, and Lya Montella. "Oncogene Amplification as an Incidental Finding in FISH Testing for Gene Rearrangements in Lymphoid Hematopoietic Neoplasms." Blood 118, no. 21 (November 18, 2011): 2505. http://dx.doi.org/10.1182/blood.v118.21.2505.2505.

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Abstract Abstract 2505 Oncogene amplification resulting in overexpression, although common in solid tumors, is rare in hematopoietic neoplasms. This is particularly true in lymphoid neoplasms compared to AML where MYC, MLL or RUNX1 (AML1) amplification has been mostly seen, and to CML where BCR/ABL fusion gene amplification has been also reported. Typically, lymphoid neoplasms are tested at diagnosis by FISH for specific reciprocal chromosome translocations that lead to overexpression of deregulated oncogenes such as BCL1, BCL2, BCL6 and MYC in B-cell lymphoma and myeloma or BCR/ABL gene fusion in ALL. Nevertheless, we have unexpectedly seen oncogene amplification from time to time in our FISH lab. To study the incidence of gene amplification and its diagnostic and clinical implications, we retrospectively analyzed FISH results routinely performed on paraffin embedded lymphoma tissues, lymph nodes, bone marrow aspirates and peripheral bloods in the past three and half years using translocation probes for BCL2/IGH, BCL1/IGH, MYC/IGH and BCR/ABL and break apart probes for BCL6 and MYC. The highest amplification rate seen was in BCL2/IGH testing: 11 of the 1,710 cases were positive (0.643%). In 2 cases with follicular lymphoma (FL), BCL2 amplification presented as homogenously staining regions (hsr), one case with diffuse large B-cell lymphoma (DLBCL) showed double minutes (dmin), and two cases with FL had a pattern of combined hsr and dmin. Five cases with low grade FL intriguingly showed a similar pattern of BCL2/IGH translocation and concomitant amplification of the rearranged BCL2 as a small hsr. The remaining case diagnosed as Burkitt lymphoma (BL) was positive for MYC/IGH translocation and for BCL2 amplification present as large hsr. BCL6 amplification was observed in 4 of 1,537 cases tested (0.26%). In all these cases, amplification presented as hsr. One case diagnosed as EBV+ DLBLC was positive for MYC/IGH translocation and 3' BCL6 high level amplification. Another case with FL showed BCL6 rearrangement and 5' BCL6 amplification. BCL1 amplification with translocation was seen as hsr in 1 case with mantle cell lymphoma out of 2,898 tested. BCL1 amplification was observed in another case with plasma cell myeloma as hsr out of 3,413 tests performed. MYC gene amplification was positive in 3 of 2,186 (0.137%). One case with BL showed MYC rearrangement with a concomitant 3' deletion and 5' amplification. The second case diagnosed as B-cell lymphoma with features intermediate between DLBCL and BL showed highly amplified MYC gene as hsr. The third case was DLBCL with 15–50 copies of MYC gene per cell as dmin. Among 530 BCR/ABL tests ordered for acute leukemia or ALL, 2 (0.377%) cases with T cell lymphoblastic leukemia/lymphoma (T-ALL/LBL) showed ABL amplification as episomes (4–8 copies in one case; 6–30 in another). Both were abnormal by cytogenetics analysis, but negative for t(9;22)(q34;q11.2) and without dmin or hsr identified. Although detection rates of oncogene amplification seem to be very low with limited specific translocation probes applied to lymphoid neoplasms, they may well be higher when FISH signal patterns are analyzed more carefully. In our study, 5 of the 11 FL cases tested for IGH/BCL2 showed a peculiar pattern positive for the t(14;18)-IGH/BCL2 and a concomitant red signal amplification of BCL2, the size of which is usually small and may be overlooked under microscope. All these 5 cases had low grade FL, suggesting that oncogene amplification can be an early genomic event in lymphomagenesis. MYC gene amplification is generally considered a late stage genomic alteration. When MYC is rearranged, amplification of BCL2, BCL6 or BCL1 may need to be taken into consideration for disease stratification, or vice versa. For instance, so called “double-hit” or “triple-hit” lymphomas currently require two or three concurrent translocations for diagnosis. Oncogene amplification, equally important for deregulation/overexpression as a translocation, should be considered as a second or a third hit in diagnosis and differential diagnosis of B-cell lymphoma unclassifiable with features intermediate between DLBCL and BL. FISH is a very useful tool to identify episomal oncogene amplification. Episomes, unlike cytogenetically evident dmin and hrs, are invisible by chromosome analysis, but their detection is important as reported for integration of targeted tyrosine kinase inhibitors into chemotherapeutic regimens. Disclosures: No relevant conflicts of interest to declare.

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6

González de Villambrosia, Sonia, Mercedes Colorado, Andres Insunza, Ana Batlle, Brenda López-Pereira, Guillermo Martin, Paloma Ibarrondo, Santiago Montes-Moreno, and Eulogio Conde. "B Cell Lymphoma Unclassifiable, with Features Intermediate Between Diffuse Large B Cell Lymphoma and Burkitt Lymphoma and Diffuse Large B Cell Lymphoma NOS with Doble/Triple Translocations: Immunophenotypic Analysis." Blood 126, no. 23 (December 3, 2015): 5037. http://dx.doi.org/10.1182/blood.v126.23.5037.5037.

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Abstract Background: Diffuse large B-cell lymphoma (DLBCL) is a clinically and molecularly heterogeneous disease. We can identify two subgroups with aggressive clinical course and higher risk of treatment failure after standard therapy: B cell lymphoma unclassifiable (BCLU) with features intermediate between DLBCL and Burkitt lymphoma (BL) and B-cell lymphomas with double/triple translocation (DHL/THL). Previous reports suggest that these types of lymphomas may show a common immunophenotype, providing another tool in the challenge of their diagnosis. Objetives: To analyze the immnunophenotype (IF) of BCLU and DH/TH lymphomas by multiparametric flow cytometry and compare it with the IF of a series of cases with DLBCL and BL. Methods: we analyzed the inmunophenotype (four-color flow cytometry on a FACSCalibur flow cytometer) and cytogenetic studies (FISH to detect MYC, BCL2 and/or BCL6 rearrangement) of cases diagnosed of BCLU and DH/TH lymphomas. Control cases of DLBCL and BL were consecutively collected from our database. Fisher`s Exact test was used to compare proportions between two groups. P-values <0.05 were considered statistically significant. Results: We analyzed 23 controls (14 DLBCL and 9 BL) and 17 cases: 9 DHL (8 BCL2/MYC+ and 1 BCL6/MYC+), 3 THL (BCL2/BCL6/MYC+) and 5 BCLU (1 IGH-MYC+, 3 MYC+ and 1 unknown). Six of the 17 cases (35.3%) had decreased expression of CD19 while this was exceptional in DLBCL (1/10 P=0.073) and BL (0/9 P=0.054). All of the cases were positive for CD20 but with different intensities: only 5.9% expressed high CD20 compared to 42.9% of DLBCL (p=0.021) and 55.6% of BL (P=0.010). Most of the cases (12/17) had intermediate expression of CD20 and only 4/17 had weak expression. CD10 expression was typical in BL (100%) and frequent in the cases (82.4%), while it was only present in 20% of DLBCL (P<0.0001). CD38 expression was high in 100% of BL, 6.3% of the cases and none of DLBCL. It was intermediate in 64.7% of the cases and in 35.7% of DLBCL (P=0.015). BCL2 overexpression was detected in 57.1% of the cases; neither DLBCL nor BL (P= 0.009) had BCL2 overexpression. Conclusions: We identify a common immunophenotype in DH/TH lymphomas and BCLU: decreased expression of CD19 and CD20, CD10 expression, overexpression of BCL2 and intermediate expression of CD38. This immuphenotype may be useful for identifying cases for confirmatory cytogenetic studies. Larger studies are needed to validate these results. Disclosures No relevant conflicts of interest to declare.

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Leski, Tomasz A., Clayton C. Caswell, Marcin Pawlowski, David J. Klinke, Janusz M. Bujnicki, Sean J. Hart, and Slawomir Lukomski. "Identification and Classification of bcl Genes and Proteins of Bacillus cereus Group Organisms and Their Application in Bacillus anthracis Detection and Fingerprinting." Applied and Environmental Microbiology 75, no. 22 (September 18, 2009): 7163–72. http://dx.doi.org/10.1128/aem.01069-09.

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ABSTRACT The Bacillus cereus group includes three closely related species, B. anthracis, B. cereus, and B. thuringiensis, which form a highly homogeneous subdivision of the genus Bacillus. One of these species, B. anthracis, has been identified as one of the most probable bacterial biowarfare agents. Here, we evaluate the sequence and length polymorphisms of the Bacillus collagen-like protein bcl genes as a basis for B. anthracis detection and fingerprinting. Five genes, designated bclA to bclE, are present in B. anthracis strains. Examination of bclABCDE sequences identified polymorphisms in bclB alleles of the B. cereus group organisms. These sequence polymorphisms allowed specific detection of B. anthracis strains by PCR using both genomic DNA and purified Bacillus spores in reactions. By exploiting the length variation of the bcl alleles it was demonstrated that the combined bclABCDE PCR products generate markedly different fingerprints for the B. anthracis Ames and Sterne strains. Moreover, we predict that bclABCDE length polymorphism creates unique signatures for B. anthracis strains, which facilitates identification of strains with specificity and confidence. Thus, we present a new diagnostic concept for B. anthracis detection and fingerprinting, which can be used alone or in combination with previously established typing platforms.

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Dupont, Thibault, Zhenghong Dong, ShaoNing Yang, Ari Melnick, and Leandro Cerchietti. "Combinatorial Targeting of BCL6 and Anti-Apoptotic Proteins in Diffuse Large B-Cell Lymphoma (DLBCL) and Follicular Lymphoma (FL)." Blood 120, no. 21 (November 16, 2012): 64. http://dx.doi.org/10.1182/blood.v120.21.64.64.

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Abstract Abstract 64 BCL6 represents a survival factor in DLBCL and FL since specific BCL6 inhibitors (i.e: the peptidomimetic RI-BPI and the small molecule 79-6) kill DLBCL and transformed FL (tFL) cell lines. Our group showed that BCL2 and other anti-apoptotic genes are transcriptionally repressed by BCL6 and could be reactivated upon treatment with RI-BPI or 79-6. We also showed that BCL6 and BCL2 control distinct and non-overlapping survival pathways in these lymphomas. This suggests that blocking the function of anti-apoptotic proteins might overcome any resistance that these proteins might mediate in response to BCL6 inhibition. In addition, constitutive expression of BCL2 has been observed in DLBCL and FL cases. We therefore hypothesized that targeting both BCL6 and BCL2 would eliminate two of the most potent survival mechanisms and would translate in synergistic killing of these lymphomas. In order to test this hypothesis, we examined the proteome-wide consequence of BCL6 inhibition in a DLBCL cell line (SU-DHL6) transfected with siBCL6 by phospho-protein arrays. We found that 280 unique proteins changed their abundance after siBCL6, 40 of them related to (pro and anti) apoptosis signaling (p<0.001). By means of pathway analysis bioinformatic tools, we then identified anti-apoptotic proteins with increased abundance after siBCL6 that could be therapeutically targeted. Among these druggable proteins we found BCL2, BCL-XL, MCL-1, NEDD8, PARP1 and several ubiquitin ligases. We confirmed in independent experiments that BCL6 knockdown induced mRNA (by qPCR) and protein up-regulation (by immunobloting) of these genes in 2 additional DLBCL and 2 tFL cell lines. Treatment of these siBCL6-transfected cell lines with small molecules inhibitors of BCL2 family members (ABT-737 and oblatoclax), NEDD8 activating enzyme (MLN4924), PARP (olaparib) and proteasome (bortezomib) showed increased killing compared to each treatment alone. In order to identify rational combinatorial therapies that could be potentially translated for use in clinical trials, we performed additional studies with the BCL6 inhibitor RI-BPI that is being developed for clinical use. We first analyzed the impact of RI-BPI on the apoptosome in a panel of 6 DLBCL (SU-DHL6, Ly1, Ly7, Ly3, Ly10, SU-DHL4) and 4 tFL (DoHH2, WSU-DLCL2, Granta452, SC-1) cell lines. RI-BPI induced a profile of up-regulated pro and anti-apoptotic proteins similar to siBCL6. Because ABT-737 and obatoclax are active in DLBCL cells where apoptotic BH3 activators are neutralized by BCL2 or BCL-XL and RI-BPI treatment changes the stoichiometry of pro and anti-apoptotic proteins, we determined the post-RI-BPI BH3 profiling accordingly to the amount of BIM sequestration (by co-immunoprecipitation). Accordingly, sequential treatment of DLBCL and tFL cell lines with RI-BPI and ABT-737 or obatoclax synergistically killed BCL2/BCL-XL dependent cells (but not MCL-1 dependent cells). This effect was independent of the mutational status of BCL2, MCL1, BCL6, MYC and TP53. Olaparib was not tested in combination since most cell lines were resistant to clinically achievable concentrations of this drug. Bortezomib and MLN4924 were synergistic in most cell lines when combined with RI-BPI (as determined by isobologram analysis). The synergistic killing was associated with increase in caspase 7/3 activation (by a plate-based assay) and NFkB inhibition (by p65 DNA binding assay). This effect was independent of the cell of origin classification of the cell line (i.e. ABC vs. GCB). We then tested the combination of RI-BPI with ABT-737, MLN4924 or bortezomib in Ly1 xenograft models (n=10 mice per combination). Ly1 represents a DLBCL with 3q27 and t(14,18). We found that after 10 days of treatment, each combinatorial treatment was more effective than their individual components (p=0.02, p=0.01 and p<0.01 for RI-BPI with ABT-737, MLN4924 and bortezomib, respectively; T-test, day 10). Detailed toxicity studies revealed no toxicity excess with these combinations. In sum, our work shows that pharmacologic targeting of anti-apoptotic pathways induced by inhibition of BCL6 activity successfully sensitized DLBCL and tFL cells to apoptosis. This effect was evident in cells in which the apoptosis resistant mechanism evolved as response to BCL6 inhibition and gene de-repression as well as those with constitutive overexpression of anti-apoptotic genes. Disclosures: No relevant conflicts of interest to declare.

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Pophali, Priyanka, Lisa M. Marinelli, Rhett P. Ketterling, Reid Gregory Meyer, Ellen D. McPhail, Paul J. Kurtin, Thomas M. Habermann, and Rebecca L. King. "High Level MYC Amplification in Aggressive B-Cell Lymphomas: Is It a Marker of Aggressive Disease?" Blood 132, Supplement 1 (November 29, 2018): 1693. http://dx.doi.org/10.1182/blood-2018-99-115484.

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Abstract MYC amplification (amp) is a marker of poor prognosis in many non-hematologic malignancies. While MYC translocations in B cell lymphoma (BCL) have been extensively studied, little is known about the significance of MYC amp. Recent studies describe increased MYC copy numbers (3-10 copies/cell) to be associated with more aggressive BCL. The WHO 2017 does not include MYC amp in the definition of high-grade BCL (HGBCL) with MYC and BCL2 and/or BCL6 rearrangement ("double-hit lymphoma", DHL). However, it also states that high-level MYC amp occurring together with a MYC rearrangement, and concurrent with BCL2 rearrangement likely has a similar clinical impact as classic DHL. Although increased MYC copy number is commonly identified by routine fluorescence in situ hybridization (FISH) testing in BCL, the experience of our large cytogenetics reference laboratory suggests that high-level MYC amp, defined as uncountable MYC signals, is far less common. Therefore, we sought to characterize the clinical, pathologic and cytogenetic features of patients with BCL showing high-level MYC amp. The Mayo Clinic cytogenetic database was retrospectively reviewed for all cases of BCL with high-level MYC amp seen by FISH from January 2010 - February 2018. All FISH studies reported as MYC amp were re-reviewed by a cytogeneticist to verify the level of amp and the MYC probes involved. Pathology was reviewed by two independent hematopathologists. Clinical information was collected through chart review. Survival analysis was performed using Kaplan-Meier curves and the Wilcoxon rank-sum test. FISH analysis for MYC aberrations identified 44/9715 (0.45%) cases with high-level MYC amp. Of cases with available H&E, the most common morphology was diffuse large BCL (DLBCL) (82%; 28/34), followed by HGBCL (15%; 5/34) and plasmablastic BCL (3%; 1/34). Hans cell of origin (COO) algorithm immunohistochemistry (IHC) identified 21/25 (84%) germinal center B-cell-like (GCB), and 4/25 (16%) non-GCB cases. 21/27 (78%) cases were BCL2+ by IHC. MYC+ by IHC was ≥40% in 21/28 (75%) and <40% in 7/28 (25%) cases. 9/17 (53%) were "double expressers" (DEL) by IHC. MYC amp probe signals appeared in a cloud-like distribution (CLD) in 31 (70%) or in a single homogenous staining region (HSR) in 13 (30%) [Figure 1A]. Among 38 cases with amp in a MYC break-apart probe, 21 (55%) had amp of 5' alone, 15 (40%) of intact and 2 (5%) of the 3' probe alone. 7/44 (16%) had MYC translocations (5 IGH; 2 non-IGH). BCL2 rearrangement was seen in 15/39 (38%) cases, and BCL6 rearrangement in 3/36 (8%). Only 2/44 (4%) cases met the current WHO 2017 definition of DHL. Clinical data was available for 20 cases. Median age at diagnosis was 64.5 (range 25-88) years with M:F of 1.5:1. Only 1/14 (7%) had bone marrow while 16/18 (88.8%) had other extranodal sites of involvement (8 gastrointestinal). The clinical presentation was heterogeneous: 13 de novo, 3 post-transplant, 3 transformed from low grade and 1 mediastinal BCL. 9/14 had an elevated LDH, median 387 (225 - 2063) U/L. R-CHOP was the most common first line therapy in 12/17 (70%). At median follow-up of 18.2 (range 0.4 - 88.9) months, 9 patients had died, 3 were in relapse and 8 remained in first complete remission. Lymphoma relapse/progression was the most common cause of death in 7/9 (78%). The median overall survival (OS) was 29.3 months [Figure 1B]. There was no statistically significant difference in OS by morphologic classification (DLBCL vs HGBCL, p=0.6), double expresser (Yes/No, p=0.19), COO (GCB vs non-GCB, p=0.08), MYC amp pattern (HSR vs CLD, p=0.48), MYC amp probe (3' vs 5' vs intact, p=0.31), MYC rearrangement (Yes/No, p=0.1), or MYC amp with concurrent BCL2/BCL6 rearrangement (Yes/No ,p=0.2). To our knowledge, this is the first study to characterize the clinical, pathologic and cytogenetic features of BCL with strictly-defined high level MYC amp identified by FISH. The 5' signal alone, or the intact MYC probe are most frequently amplified, and two distinct patterns of amp can be seen. Predominant extra nodal involvement is an important clinical observation. These cases are usually DLBCL, GCB type, and infrequently have concurrent MYC/BCL2/BCL6 rearrangement. Our study suggests that BCL with high-level MYC amp may have an aggressive disease course regardless of MYC, BCL2 and BCL6 gene rearrangement status. A larger series is necessary to further understand the clinical significance of high-level MYC amp in BCL. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

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Pedersen, Mette Ølgod, Anne Ortved Gang, Tim Svenstrup Poulsen, Helle Knudsen, Anne F. Lauritzen, MajLis M. Talman, Signe Ledou Nielsen, and Peter H. Norgaard. "Concurrent BCL2 and MYC Translocations In a Prospective Cohort of Diffuse Large B-Cell Lymphomas." Blood 116, no. 21 (November 19, 2010): 319. http://dx.doi.org/10.1182/blood.v116.21.319.319.

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Abstract Abstract 319 Background: Concurrent chromosomal translocations involving the BCL2 and MYC protooncogenes, so-called double-hit, is found both in diffuse large B-cell lymphoma (DLBCL) and in a newly defined B-cell lymphoma category with features overlapping between DLBCL and Burkitt lymphoma (BCLU, 2008 WHO classification). Few studies have been published on series of double-hit B-cell lymphomas, and to our knowledge only retrospective series, reporting an average frequency of around 5%. Therefore some authors suspected that the frequency of double-hit translocations was underestimated. In addition to unanimous reports of highly aggressive clinical behaviour; poor outcome and resistance to chemotherapy, double-hit lymphomas had GCB immunophenotype (Hans), varying morphology from classical Burkitt like to DLBCL-NOS and mostly high proliferation rates (Ki-67). Purpose: We conducted a prospective study of DLBCL to evaluate the frequency of double-hit BCL2/MYC translocations in DLBCL. Secondly, we wanted to analyse if any pathologic and/or clinical features correlated with the presence of a double-hit in order to evaluate the need for routine genetic analysis of large B-cell lymphomas in prognostic stratification. Materials and methods: All patients diagnosed with DLBCL or BCLU at the Haematopathology Section at Copenhagen University Hospital in Herlev were prospectively collected throughout 2009. Tumours were classified according to their morphology (2008 WHO classification), immunohistochemistry (CD10, BCL6, MUM1, BCL2, Ki-67) and FISH (BCL2, BCL6 and MYC translocations). Clinical data were collected from patient files. Result: Double-hit BCL2/MYC translocations were detected in 9 of 93 cases (10%); 7 DLBCL, 1 BCLU, 1 unclassified. All double-hit DLBCL were GCB immunophenotype and showed varying morphology. Ki-67 index ranged from 15–95%. Interestingly, 2 double-hit cases were late relapses (primary double-hit). Characteristic clinical parameters included a high International Prognostic Index (IPI) score, a high stage and an extranodal presentation. Discussion and conclusion: In this prospective cohort of DLBCL patients the incidence of BCL2/MYC double-hit was 10%. This suggests that double-hit is more frequent in DLBCL than previously estimated. Double-hit lymphomas had GCB-immunophenotype but could not be identified by morphology or proliferation rate. Therefore if these patients should be identified due to an inferior prognosis (which we could not significantly establish due to limited observation time) routine FISH analysis for double-hit translocations should be performed in all patients with BCLU or DLBCL of GCB-subtype. Disclosures: No relevant conflicts of interest to declare.

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Shivam, Saloni, Mansour El-Matbouli, and Gokhlesh Kumar. "Kinetics of Parasite-Specific Antibody and B-Cell-Associated Gene Expression in Brown Trout, Salmo trutta during Proliferative Kidney Disease." Biology 10, no. 12 (November 28, 2021): 1244. http://dx.doi.org/10.3390/biology10121244.

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Tetracapsuloides bryosalmonae, a myxozoan endoparasite often causes chronic infection in brown trout. Antiparasite immunity mediated by antibodies and B cells is known as an important determinant of host survival and parasite proliferation during chronic infections. Accordingly, studying their time course during proliferative kidney disease (PKD) might be helpful in improving our understanding of its chronic nature. Therefore, we conducted this study to examine parasite specific serum antibody and B-cell-mediated response in laboratory-infected brown trout at different time points. Brown trout were exposed to the spores of T. bryosalmonae, derived from infected bryozoans. Samples were collected at different time points and processed for indirect ELISA, histopathology, and qRT-PCR. T. bryosalmonae specific antibody was detected at 4 weeks post exposure (wpe) and it persisted until 17 wpe. Additionally, the expressions of C4A, CD34, CD79A, BLNK, CD74, BCL7, and CD22 were differentially regulated in the important immune organs, kidney and spleen. To our knowledge, this is the first study addressing anti-T. bryosalmonae antibody response in brown trout at different time points. The results from this study provide valuable insights into the processes leading to changes in B cell development, inflammation and antibody production during the course of PKD in brown trout.

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Palathingal Bava, E., W. liu, Y. Shen, X. Fang, J. Carey, J. C. Gomez-Gelvez, K. Inamdar, and S. Ghosh. "Composite Lymphoma Comprising of BCL2 Rearrangement Negative, CD23 Positive Follicle Center Cell Lymphoma and Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: A Case Report." American Journal of Clinical Pathology 162, Supplement_1 (October 2024): S75—S76. http://dx.doi.org/10.1093/ajcp/aqae129.167.

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Abstract Introduction/Objective BCL2 rearrangement negative, CD23-positive follicle center cell lymphoma (BCL2 neg CD23 pos FCL) is a rare, recently described provisional entity in International Consensus Classification (2022). It has a predominantly diffuse growth pattern and often involves inguinal region. The molecular profile includes a high frequency of STAT6 and CREBBP co-mutation as well as 1q gain and a recurrent 1p36 loss/TNFRS14 abnormalities. We describe a composite tumor comprising of a rare entity BCL2 neg CD23 pos FCL and Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL). To the best of our knowledge this is the first reported case description of this co-occurrence. Methods/Case Report A 59 y/o woman presented with right cervical and axillary lymphadenopathy (upto 1.6 cm). Sections showed partial effacement of nodal architecture by interfollicular and diffuse proliferation of atypical lymphoid cells. The interfollicular areas were comprised of a monotonous population of small lymphocytes. Immunohistochemical stains performed showed that the interfollicular CD20+ PAX5+ atypical lymphoid cells coexpressed CD5, CD23, BCL2 and LEF1 and were negative for CD10, BCL6, CD3, and SOX11, with MIB1 of 5-10%. Based on these, a diagnosis of CLL/SLL was made. Admixed with the CLL/SLL, a second neoplastic B-cell component that distorted nodal architecture was also identified. It composed of a diffuse proliferation of intermediate sized lymphoid cells with a centrocytic/centroblastic morphology. This smaller population of small to intermediate sized B cells expressed CD10, BCL6, and CD23 with a MIB1 proliferation index of ~30%. This population was CD5 and BCL2 negative. CD21 showed residual follicular dendritic cell meshworks. SOX11 and BCL1 were negative. Therefore, a diagnosis of BCL2 neg CD23 pos FCL was made. Flow cytometry showed two distinct populations of monotypic B-cells, one CD5-positive and the other CD10-positive. FISH studies were negative for BCL2 and BCL6 rearrangements as well as del1p36. Cytogenetics was positive for trisomy 12, supporting CLL/SLL. Next Generation Sequencing showed Tier 1 / 2 mutations in STAT6, TNFRSF14, CREBBP, and FOXO1, supporting BCL2 neg CD23 pos FCL. Hence, this represents a unique case of composite CLL/SLL and BCL2 neg CD23 pos FCL. B cell gene rearrangement showed 2 distinct clones confirming 2 separate B cell lymphomas. Results (if a Case Study enter NA) NA Conclusion Here, we describe a composite CLL/SLL and BCL2 rearrangement negative, CD23 positive, FCL never previously described in literature.

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Piovan, Erich, Masumichi Saito, Katia Basso, Urban Novak, Qiong Shen, Laura Pasqualucci, and Riccardo Dalla-Favera. "Direct Transcriptional Repression of BCL2 by BCL6 in Germinal Centre B Cells and Its Disruption in B Cell Lymphomas with BCL2 Locus Alterations." Blood 112, no. 11 (November 16, 2008): 296. http://dx.doi.org/10.1182/blood.v112.11.296.296.

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Abstract The human proto-oncogene BCL6 encodes a BTB/POZ-zinc finger transcriptional repressor that is required for germinal centre (GC) development and is expressed in the majority of normal GC B cells and in the majority of B cell lymphoma (B-NHL), including follicular lymphoma (FL) and a subset of diffuse large B cell lymphomas (DLBCLs). Deregulation of BCL6, by chromosomal translocation or somatic hypermutation, is implicated in the pathogenesis of B-NHL. The precise function of BCL6 in GC development and lymphomagenesis is still unclear also due to the very few direct BCL6 target genes that have been identified. In order to identify physiologically relevant BCL6 direct target genes, we used a novel approach combining high-throughput biochemical (ChIP-on-chip), bioinformatics (ARACNe) (Basso et al., Nature Genetics, 2005) and gene expression profile analysis (Klein et al., Proc. Natl. Acad. Sci., 2004) of normal GC B cells. The results (see abstract by Saito et al.) have identified a core of bona fide target genes whose promoter is bound by BCL6, whose transcription is dynamically linked to BCL6, and whose expression is down-regulated in GC B cells. Among the genes meeting these stringent criteria, we found BCL2, encoding the anti-apoptotic molecule whose expression is deregulated by chromosomal translocations or gene amplification in the majority of FL and in a subset of DLBCL. Further investigations showed that BCL6 represses BCL2 transcription by binding specific DNA sites within the BCL2 promoter region. Suppression of BCL6 expression via specific siRNAs leads to increased levels of BCL2, and, conversely, constitutive BCL6 expression prevents B cell receptor (BCR)-induced upregulation of BCL2 in B cells. Consistent with a physiological role for BCL6- mediated BCL2 suppression, immunohistochemical analysis shows that BCL2 expression is absent in GC B cells where BCL6 is highly expressed. Notably, the comparative analysis of BCL6 and BCL2 expression in B-NHL cell lines showed a conserved inverse correlation between BCL6 and BCL2 levels in cell lines carrying a normal BCL2 locus. However, cell lines carrying chromosomal translocations or amplifications affecting the BCL2 gene displayed the pathologic co-expression of both proteins, suggesting that the alterations affecting the BCL2 locus prevent BCL6-mediated suppression. These results indicate that one critical role of BCL6 is the modulation of antiapoptotic function in GC B cells via BCL2 transcriptional repression, suggesting a mechanism by which B cells may die in the GC if not rescued by BCR and CD40 engagement, both of which downregulate BCL6 while inducing BCL2 expression. Alterations of the BCL2 locus may contribute to lymphomagenesis by making the gene resistant to suppression by BCL6, and therefore allowing B cells to avoid apoptosis in the absence of antigen- and T-cell-mediated rescue.

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Navarro, Jose-Tomas, Maria Joao Baptista, Alejandra Martinez-Trillos, Gustavo Tapia, Jose Angel Hernandez-Rivas, Olga Garcia, Anna Muñoz-Marmol, et al. "Lymphomas With MYC-Translocation Other Than Burkitt’s Have An Aggressive Presentation and Poor Response To Immunochemotherapy: Study Of 34 Cases." Blood 122, no. 21 (November 15, 2013): 5083. http://dx.doi.org/10.1182/blood.v122.21.5083.5083.

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Abstract Introduction MYC translocations involving chromosome 8q24 can occur in a wide variety of B-cell lymphomas other than Burkitt’s lymphoma (BL), especially diffuse large B-cell lymphoma (DLBCL) and B-cell lymphoma unclassifiable with intermediate features between DLBCL and BL (BCLU). These lymphomas can harbor additional translocations of BCL2 and/or BCL6, that have been referred to as double and triple-hit lymphomas. MYC positive lymphomas other than BL are not well characterized and the standard treatment has to be established. Aim The objective was to study the clinic-biological characteristics and prognosis of a series of lymphomas with MYC-translocation other than BL. Methods Retrospective study of patients with MYC-translocation other than BL treated in three hospitals of Spain between 2003 and 2012. Cases with diagnosis of BL, Burkitt’s-like lymphoma and any other with MYC-translocation were reviewed and classified according to the WHO 2008 criteria. The status of MYC, BCL2 and BCL6 genes were evaluated in all cases by fluorescent in situ hybridization (FISH) using dual-colour break-apart commercial probes (LSI MYC DC BA, LSI BCL6 DC BA and LSI BCL2 DC BA; Abbot Molecular, Abbot Park, IL, USA) on whole tissue sections of formalin-fixed paraffin-embedded tissue. Main clinical and biological data were collected from the records. Results Between 2003 and 2012, 34 patients with a median follow-up of 1.9 years (range 0.7-9.7) were included. Median age was 59.5 years (range 36-83) and 21 (62%) were male. ECOG score at diagnosis was ≥2 in 14 patients (42%), 16 (49%) had ≥2 extranodal sites involved, serum LDH was elevated in 24 out of 32 (75%), Ann Arbor stage III/IV in 24 (73%) and B symptoms were present in 18 (56%). IPI was high or intermediate/high in 19 out of 32 (59%). Eighteen patients (53%) presented with a mass (13 abdominal location). Twenty-four cases were diagnosed with DLBCL and 10 with BCLU. Conventional cytogenetics showed a complex karyotype in the 9 studied cases. MYC rearrangement alone without BCL2 or BCL6 rearrangements was observed in 13 (38%) cases, 15 were double-hit, and 6 triple-hit lymphomas. There were no differences between patients with MYC translocation alone and patients with double or triple-hit, regarding the clinical and biological characteristics. Moreover, there were no clinical and biological differences between patients with DLBCL and those with BCLU. Twenty-one cases were treated with R-CHOP (19 DLBCL and 2 BCLU), and 13 with a specific treatment for BL (Burkimab) (8 BCLU and 5 DLBCL) (P=0.002). Complete response (CR) was achieved in 14 out of 32 (44%) cases (9 out of 21 [45%] treated with R-CHOP and 5 out of 13 [42%] with Burkimab). Two patients died during chemotherapy. Six out of the 9 patients in CR to R-CHOP relapsed, but none of the 5 patients in CR to Burkimab did it. The overall survival (OS) probability and progression free survival (PFS) at 2 years, (95% CI) for the whole series were 32% (14%, 50%) and 21% (6%, 36%) respectively. The two-year OS and PFS probabilities were not significantly different between patients treated with Burkimab and those treated with R-CHOP: 62% (95% CI: 36%, 88%) versus 28% (95% CI: 8%, 48%) for OS (P=0.67); and 46% (95% CI: 19%, 73%) versus 15% (95% CI: 0%, 31%) for PFS (P=0.549), respectively. Conclusions Lymphomas with MYC translocation other than BL present aggressive characteristics at diagnosis and have poor response to immunochemotherapy. Supported in part by grants EC11-041 and RD12/0036/0029 RTICC from Instituto Carlos III, Spain Disclosures: Lopez-Guillermo: Roche: Membership on an entity’s Board of Directors or advisory committees.

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Botto, Barbara, Domenico Novero, Annalisa Chiappella, Mattia Novo, Alessia Castellino, Chiara Ciochetto, Giovanni Cametti, et al. "The Prognostic Value of MYC, BCL2 and BCL6 Overexpression Evaluated By Immunohistochemistry (IHC) in De-Novo Diffuse Large B Cell Lymphoma (DLBCL) Treated with Rituximab-CHOP." Blood 124, no. 21 (December 6, 2014): 2964. http://dx.doi.org/10.1182/blood.v124.21.2964.2964.

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Abstract Introduction : MYC, BCL2 and BCL6 overexpression, assessed by IHC, with the latter conferring a better prognosis, have been reported to be a prognostic factor in DLBCL, but data are not consistent and sometimes contradictory. The aim of the present study was to assess the prognostic impact of overexpression of MYC, BCL2, and BCL6 in a retrospective cohort of de-novo DLBCL, selected for an high proliferation index (MIB1 ≥70%), treated consecutively with R-CHOP regimen. Methods: Patients with de-novo DLBCL diagnosed between January 2010 and December 2013 were included into the study. Inclusion criteria were: high proliferation index MIB1 ≥ 70% and a full course of R-CHOP regimen. Paraffin-embedded tumor samples were collected and investigated using immunohistochemistry (IHC) for MYC, BCL2 and BCL6. Fluorescence in situ hybridization (FISH) is ongoing. MYC/BCL2+ or MYC/BCL6+ double expression cases were identified if they had rearrangements of MYC and BCL2 or BCL6. MYC immunochemistry was done on TMA sections using the antibody clone Y69. BCL2 and BCL6 staining had been evaluated previously at diagnosis. Tumor cells were defined positive for MYC and BCL2 or BCL6 protein expression by immunostaining if >40%, >40% and >25% of cells showed positive expression, respectively. Progression free survival curves (PFS) were estimated using the Kaplan-Meier method and compared between groups using the log-rank test and Cox models. Results : One hundred and sixty seven patients are evaluable for clinical characteristics and 69/167 had paraffin embedded tumor samples available for immunohistochemistry at the time of present analysis. Clinical characteristics of the 69 cases were: median age 66 years (IQR 57;73), 45 (65%) male, 47 (68%) stage III-IV, 35 (54%) with elevated LDH levels and 46 (67%) at International Prognostic Index (IPI) high intermediate or high risk. Overexpression of MYC was detected in 28 cases (41%), 50 (72%) and 38 (55%) showed BCL2 and BCL6 overexpression respectively. Nineteen (28%) cases showed MYC/BCL2+ and 17 (25%) MYC/BCL6+ double expression. With a median follow up of 26 months, the median 2-years PFS was 59%. Overexpression of MYC and BCL2 proteins and low expression of BCL6 were associated with an inferior 2-years PFS in univariate analysis: MYC- vs MYC+ 64% vs 55%; BCL2- vs BCL2+ 71% vs 56%; BCL6+ vs BCL6- 61% vs 54%. In a Cox multivariate regression model adjusted for IPI and age, MYC overexpression, BCL2 positivity and BCL6 negativity showed prognostic relevance as significant independent indicators with different risk (Hazard ratio 2.53 for MYC+, 2.08 for BCL2+ and 1.62 for BCL6-). Established that the three variable contributed with different risk in the multivariate analysis, an IHC sum additive score of 0-5 was calculated proportionally to the coefficient estimated (coefficient [Log hazard ratio] 0.92 for MYC+, 0.73 for BCL2+ and 0.48 for BCL6-), assigning an individual risk of 2 points for MYC or BCL2 positivity and 1 point for BCL6 negativity. Two years-PFS was significantly different between all separate groups (Hazard ratio for unit increase 1.57 95% CI 1.11-2.22, p=0.01). After pooling scores 0-1 (with or without BCL6), 2 (presence of MYC or BCL2 only), and 3-4-5 (MYC+/BCL6-, BCL2+/BCL6-, MYC+/BCL2+, MYC+/BCL2+/BCL6-) 2-yrs PFS rates were different across the three groups: 100% vs 64% vs 50% (log rank p= 0.04) (figure 1). Conclusion: Our data showed, with the limits of a small sample size, that MYC overexpression alone or with high expression of BCL2 and/or low expression of BCL6 correlates with a worse prognosis independently by IPI score in a cohort of DLBCL selected for high proliferation index and treated with R-CHOP. Assessment of MYC, BCL2 and BCL6 expression by IHC represents a rapid, inexpensive, and reproducible technique. These results need to be confirmed in our complete series of 167 patients (analysis ongoing) and validated prospectively in a larger cohort, using standardized staining and scoring methodologies. Thus, MYC and BCL2 represent relevant biomarkers that should be tested in future clinical trials using novel effective and targeted agents in order to improve the prognosis of DLBCL. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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Yang, Ge, Pin Wan, Qi Xiang, Shanyu Huang, Siyu Huang, Jun Wang, Kailang Wu, and Jianguo Wu. "E3 Ubiquitin Ligase ASB17 Promotes Apoptosis by Ubiquitylating and Degrading BCLW and MCL1." Biology 10, no. 3 (March 18, 2021): 234. http://dx.doi.org/10.3390/biology10030234.

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Apoptosis is a very important process of cell death controlled by multiple genes during which cells undergo certain events before dying. Apoptosis helps to clean the unnecessary cells and has critical physiological significance. Altered apoptosis results in a disorder of cell death and is associated with many diseases such as neurodegenerative diseases and cancers. Here, we reported that the ankyrin repeat and SOCS box protein 17 (ASB17) was mainly expressed in the testis and promoted apoptosis both in vivo and in vitro. Analyzing ASB17-deficient mice generated by using the CRISPR/Cas9 system, we demonstrated that ASB17 deficiency resulted in the reduction of apoptosis in spermatogenic cells, but it did not affect the development of spermatozoa or normal fertility. Next, in an in vivo model, ASB17 deficiency prevented the apoptosis of spermatogonia induced by etoposide in male mice. We noted that ASB17 promoted apoptosis in a caspase-dependent manner in vitro. Moreover, ASB17 interacted with the members of the BCL2 family, including BCL2, BCLX, BCLW, and MCL1. Interestingly, ASB17 specifically degraded the two anti-apoptotic factors, BCLW and MCL1, in a ubiquitylation-dependent fashion. Collectively, our findings suggested that ASB17 acted as a distinct positive regulator of cell apoptosis.

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Hildebrand, Johannes Adrian, Sarah Haebe, Verena Passerini, Michael Heide, William Keay, Louisa Adolph, Lukas Ulrich, et al. "Lysosomal Membrane Permeabilization Sensitizes Ctss-Hyperactive Tumors to BCL2-Targeting Therapies." Blood 142, Supplement 1 (November 28, 2023): 4358. http://dx.doi.org/10.1182/blood-2023-174384.

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Hyperactivity of the cysteine protease cathepsin S (CTSS) -either through Y132 mutations or amplification/overexpression- is a recurrent alteration in follicular lymphoma (FL) and promotes tumor growth by inducing a supportive immune microenvironment (Bararia et al, 2020). Of note, patients with CTSS-hyperactive FL had better outcomes with standard therapies, suggesting that CTSS-hyperactivity can sensitize tumors to treatment. CTSS hyperactivity has also been reported in other B cell lymphomas (BCLs) (Dheilly et al, 2020) and solid cancers (Olson & Joyce, 2015). CTSS is mainly localized intralysosomally but can be released into the cytosol by lysosomal membrane permeabilization (LMP). Low level LMP can occur spontaneously (e.g., during cell division) and can be enhanced by treatment. Unlike other cathepsins, cytosolically released CTSS maintains its enzymatic activity at non-acidic pH. Thus, we aimed to (i) identify the determinants of the cytosolic CTSS activity, (ii) determine its impact on the regulation of apoptosis, and (iii) study LMP as a therapeutic approach for CTSS-hyperactive tumors. First, we accrued biochemical, functional, and clinical data supporting the role of cystatin B (CSTB) as a clinically relevant endogenous CTSS inhibitor in BCLs. Through unbiased and complementary proteomics (BioID2 labelling and co-IP followed by LC-MS/MS) we identified CSTB as a direct CTSS-interacting protein (8-fold enriched in the BCL cell line Karpas422 engineered to express CTSS wild type (WT) or Y132D vs CTSS knock-out (KO), P=0.0002). Single-cell RNA-Seq of primary FL (N=10) showed significantly higher CSTB expression in FL cells compared to normal B cells ( P=0.004). Moreover, shRNA mediated knock-down (k/d) of CSTB increased the overall cathepsin activity in BCL cell lines (N=8) by 1.5 to 5.5-fold, most notably in CTSS-hyperactive cells ( Fig A, top). We next employed LMP-inducing tool compounds (LLOMe) and clinically used drugs or analogs (desipramine, hexamethylene amiloride) to release cathepsins into the cytosol. CTSS-hyperactive Karpas422 were significantly more sensitive to LMP-inducing treatments compared to native cells (1.5 to 10-fold reduction of IC50). Importantly, CTSS hyperactivity and CSTB k/d increased LMP-mediated cell killing ( Fig A, bottom). Thus, the cytosolic CTSS/CSTB interaction determines the net cytosolic cathepsin activity and sensitivity of cells to undergo LMP-induced cell death. Next, we hypothesized that LMP-induced cytosolic CTSS hyperactivity could prime BCLs towards apoptosis. We used BH3 profiling to functionally quantify the dependencies and interactions of BCL2 family members in BCLs with and without CTSS hyperactivity. In Karpas422 cells expressing CTSS Y132D, LMP increased overall apoptotic priming and dependencies on the anti-apoptotic proteins MCL-1 (delta priming >30 % at 10 µM, P=0.04), BCL-xL (>45 % at 10 µM, P=0.0006) and BCL2 (> 45 % at 0.5 and 1 µM, P=0.0001). We hypothesized that BCL2 family members are proteolytically cleaved by cytosolic CTSS. Indeed, e.g., BCL2 protein levels were 2.5 to 3.5-fold lower in LLOMe-treated Karpas422 cells with CTSS-hyperactivity compared to CTSS KO, and CSTB k/d further decreased BCL2 levels. To validate CTSS-mediated cleavage of BCL2, we purified FLAG-tagged BCL2 and CTSS WT and Y132D. CTSS WT efficiently cleaved BCL2 in vitro <1 hour at the top ranked predicted cleavage site and the reaction rate increased 1.3-fold for CTSS Y132D. Finally, we hypothesized that LMP sensitizes cells to BCL2-targeting therapies ( Fig B). The combination of LLOMe-induced LMP and the BCL2 inhibitor venetoclax (VEN) showed increased cytotoxicity in CTSS-hyperactive Karpas422 cells compared to monotherapy and CSTB k/d enhanced this phenotype ( Fig A, bottom). We assessed cathepsin activities and generated dose-response curves for VEN with and without LLOMe-induced LMP in 15 primary CLL samples. Thereof, 12 samples had intermediate or high cathepsin activities and LLOMe-induced LMP increased their sensitivity to VEN, including a VEN-resistant sample in which the IC50 decreased to <3 nM. In summary, we show that CSTB is a functionally relevant inhibitor that determines the net activity of LMP-released cytosolic CTSS. Furthermore, LMP-inducing therapies may be a promising approach to sensitize CTSS-hyperactive tumors towards apoptosis by proteolytic cleavage of BCL2 family members.

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Patel, Priyank P., Pallawi Torka, Vishala T. Neppalli, George Deeb, Sheila N. J. Sait, AnneMarie W. Block, Seema A. Bhat, Myron S. Czuczman, and Francisco J. Hernandez-Ilizaliturri. "Intense Cytarabine-Based Chemo-Immunotherapy, Central Nervous System (CNS) Prophylaxis and Early High-Dose Chemotherapy and Autologous Stem Cell Support (HDC-ASCS) in First Remission Are Associated with an Improved Clinical Outcome in Double-Hit (DHL)/Triple-Hit (THL) Diffuse Large B-Cell Lymphoma (DLBCL)." Blood 124, no. 21 (December 6, 2014): 3031. http://dx.doi.org/10.1182/blood.v124.21.3031.3031.

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Abstract Based on molecular studies, DLBCL is now further divided in three subtypes with distinct pathogenesis and clinical outcomes. Fluorescence in situ hybridization (FISH) studies identified a subgroup of DLBCL with a poor clinical outcome harboring concurrent gene rearrangements of the MYC, BCL2 and/or BCL6 proto-oncogenes leading to the over-expression of c-Myc, Bcl-2 and Bcl-6, inferior response rates to rituximab-based chemotherapy, and a shorter progression-free survival (PFS)/overall survival (OS). This group of patients is now categorized as double-hit (DHL) or triple-hit (THL) DLBCL. Immunohistochemistry (IHC) studies suggested that DLBCL patients with over-expression of Bcl-2 and c-Myc proteins exhibit a similar clinical course than those patients with DHL/THL. Alternative transcriptional (i.e. gene amplification or chromosomal gain) or post-translational regulatory mechanisms (yet to be defined) may be responsible for the over-expression of c-Myc, Bcl-2, or Bcl-6 in some patients with DHL/THL phenotype. The appropriate therapy for DHL/THL remains to be defined, but retrospective studies had demonstrated that at standard doses of R+CHOP are suboptimal. In order to study the impact of more aggressive therapeutic approaches in the management of DHL/THL, we retrospectively evaluated our single institution outcome experience over the last 14 years. Using the lymphoma translational database that includes 611 DLBCL patients, we identified 24 patients (M=13/F=11) (4%) with FISH-confirmed DHL/THL DLBCL. Demographic characteristics, clinical data, treatment history in the front line (including the use of CNS prophylaxis, high-dose chemotherapy and autologous stem cell support [HDC-ASCS] or allogeneic bone marrow transplant [allo-BMT]) were collected. In addition, response rate, PFS and OS were calculated. Since the first case-reports were published, we observed a steady increase in the number of DHL/THL patients at our Institution (7 vs. 18 cases before or after 2011) which represents an increasing medical awareness of this new clinical entity. The mean age at diagnosis was 62 years (25 to 85 years), most of them Caucasians (N=22). The median Ki67 proliferation index was 90%. Using the Han’s algorithm, 11 of the DHL/THL were categorized as germinal center B-cell like (GCB), 6 patients as non-GCB, and 7 patients could not be classified. By FISH studies, 58% were DHL (involvement of MYC and BCL2 [N=22] or BCL6 [N=10]) and 42% THL (involvement of MYC, BCL2 and BCL6, N=10). Gene rearrangements involving MYC, BCL2, or BCL6 were observed in 18 patients and MYC, BCL2 or BCL6 gain in 6. Clinically, 95% of the patients presented with stage III/IV, 67% with High-intermediate/High IPI score, and 79% of the patients had extranodal disease. Front-line chemo-immunotherapy included 1) standard doxorubicin-containing regimens: R+CHOP (N=10) or R-EPOCH (N=7), or 2) intensified regimens: R-DHAC (N=2) and R+HyperCVAD/R+HDMTXCytarabine (N=4). Prophylaxis IT chemotherapy was administered to 16 (67%) patients. The complete remission (CR) rate was 62.5% and 29% of the patients underwent HDC-ASCS (N=4)/allo-BMT (N=2) in first (N=2) or second-remission (N=4). In this group of patients, the use of intensified regimens was associated with a non-statistically significant improvement is OS when compared to R+CHOP/R+DA-EPOCH (OS at 3 years of 85.7% vs. 58%). Similarly, an improvement in OS was observed among patients receiving HDC-ASCT/allo-BMT as consolidation (71% vs. 60%, P=0.27). Of interest, CNS prophylaxis was associated with an improvement in OS at 3 years (81% vs. 37%, P=0.032). No differences in clinical outcomes were observed between DHL/THL harboring gene-rearrangements vs. gene gain. In summary, our single institution experience suggests that DHL/THL are increasingly being recognized as more aggressive sub-types of DLBCL with a dismal outcome with conventional therapeutic approaches. A high-index of suspicion should be raised and testing for DHL/THL in those DLBCL presenting with advance stage, multiple extra-nodal site of disease, and an elevated Ki67 index should be done. The accurate identification of DHL/THL patients is necessary, as they appear to benefit from rituximab-based intensified cytarabine-containing regimens, CNS prophylaxis and HDC-ASCT/allo-BMT consolidation. Disclosures No relevant conflicts of interest to declare.

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Swerdlow, Steven H. "Diagnosis of ‘double hit’ diffuse large B-cell lymphoma and B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma: when and how, FISH versus IHC." Hematology 2014, no. 1 (December 5, 2014): 90–99. http://dx.doi.org/10.1182/asheducation-2014.1.90.

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Abstract Identification of large B-cell lymphomas that are “extra-aggressive” and may require therapy other than that used for diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS), is of great interest. Large B-cell lymphomas with MYC plus BCL2 and/or BCL6 rearrangements, so-called ‘double hit’ (DHL) or ‘triple hit’ (THL) lymphomas, are one such group of cases often recognized using cytogenetic FISH studies. Whether features such as morphologic classification, BCL2 expression, or type of MYC translocation partner may mitigate the very adverse prognosis of DHL/THL is controversial. Classification of the DHL/THL is also controversial, with most either dividing them up between the DLBCL, NOS and B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma (BCLU) categories or classifying at least the majority as BCLU. The BCLU category itself has many features that overlap those of DHL/THL. Currently, there is growing interest in the use of MYC and other immunohistochemistry either to help screen for DHL/THL or to identify “double-expressor” (DE) large B-cell lymphomas, defined in most studies as having ≥40% MYC+ and ≥50%-70% BCL2+ cells. DE large B-cell lymphomas are generally aggressive, although not as aggressive as DHL/THL, are more common than DHL/THL, and are more likely to have a nongerminal center phenotype. Whether single MYC rearrangements or MYC expression alone is of clinical importance is controversial. The field of the DHL/THL and DE large B-cell lymphomas is becoming more complex, with many issues left to resolve; however, great interest remains in identifying these cases while more is learned about them.

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Carey, Christopher Daniel, Daniel Gusenleitner, Zhang Xuan, Aliyah R. Sohani, Olga Weinberg, Hongbo Yu, Ben Chen, et al. "Resolving the Biological Heterogeneity of B-Cell Lymphoma, Unclassifiable, with Features Intermediate Between DLBCL and BL (BCL-U) Using Quantitative Profiles of Oncogenic Signaling Networks." Blood 126, no. 23 (December 3, 2015): 3903. http://dx.doi.org/10.1182/blood.v126.23.3903.3903.

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Abstract BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL) have characteristic cellular, phenotypic, and genetic characteristics that reflect their distinctive biology. These distinctions are attributable, in part, to differential activity of defined oncogenic signaling pathways, including TCF3/ID3, NFkB, MYC, and BCL2 (Carey et al, JMD, 2015). B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and BL (BCL-U) encompasses a group of tumors with ambiguous features and likely heterogeneous biology. We used targeted gene expression profiling and a molecular classifier based on the major signaling networks active in DLBCL and/or BL to address the biological heterogeneity of BCL-U. METHODS: We analyzed RNA isolated from paraffin-embedded tissue sections of 72 aggressive B-cell lymphomas (BCLs) selected according to original pathological diagnoses of BL (12 cases), DLBCL (20 cases), BCL-U (22 cases), and 'large B-cell lymphoma with high grade features' (18 cases). Sixteen genetic double hit lymphomas (DHLs) that combine a MYC -rearrangement with a BCL2 - and / or BCL6 -rearrangement were included in the series. Five hematopathologists reviewed each case to separate those with a consensus diagnosis from those where there was no consensus. We profiled the RNA in 2 laboratories and used a molecular diagnostic classifier to provide a "probability score" for the diagnosis of BL or DLBCL. Cases with a diagnostic score of >0.75 were categorized as "molecular BL" (mBL), between 0.25 and 0.75 as intermediate between BL and DBLCL (intBCL), and ≤0.25 as "molecular DLBCL" (mDLBCL). Finally, we compared the results of expert review with the results of molecular classification. RESULTS: Eight of 8 consensus diagnoses of BL classified molecularly as mBL and 13/13 consensus diagnoses of DLBCL classified as mDLBCL (100%). Seventy of 72 cases (97.2%) were molecularly classified with consensus upon profiling in 2 laboratories. Consensus pathological diagnoses that agreed with the original diagnoses were reached in 6/9 BL (66.7%), 6/12 DLBCL (50%) and 2/22 BCL-U (9.1%). Cases classified as BCL-U by two or more expert pathologists (29) were assigned to all molecular diagnostic categories, including 11 (15.7%) to mBL, 12 (41.4%) to intBCL, and 6 (20.7%) to mDLBCL. Similarly, subsets of DHLs with molecular consensus (14) classified as mBL (21.4%), intBCL(64.3%) and mDLBCL (14.3%). Among cases without a consensus pathological diagnosis, 9 (34.6%) were classified as mBL with high probability, 14 (53.8%) were classified as mDLBCL with high probability, and 3 (11.5%) were classified as intBCL. CONCLUSIONS: We find that the quantitative analysis of oncogenic signaling pathways using targeted expression profiling accurately and reproducibly 1) segregates BL from DLBCL, 2) assigns a subset of BCLs that are not diagnosed with consensus by traditional methods to mBL and mDLBCL and 3) identifies subsets of DHLs with molecular signatures of mBL, intBCL, and mDLBCL. Targeted molecular profiling and molecular classification of aggressive B-cell lymphomas is a useful new ancillary test in the diagnostic evaluation of aggressive B-cell lymphomas that provides a biological framework for designing rational treatment strategies. Figure 1. Figure 1. Disclosures Rodig: Perkin Elmer: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Research Funding.

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Walia, Jasmit, Timothy Daly, Ali Tahir, Melissa Wilson, and Kunal Bhagatwala. "A case of triple hit lymphoma and rapid deterioration." Journal of Case Reports and Images in Oncology 9, no. 1 (March 21, 2023): 8–11. http://dx.doi.org/10.5348/100118z10jw2023cr.

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Triple hit lymphomas (THL) comprise a rare, heterogenous group of lymphomas and like many B-cell lymphomas, chromosomal translocations are biologic and diagnostic hallmarks of disease. Traditionally referred to as a subset of double hit lymphomas (DHL) in literature, THLs characteristically involve chromosomal rearrangements of c-MYC, BCL-2, and BCL-6 oncogenes. Many case series of high-grade B-cell lymphoma, especially MYC/BCL2 double hit lymphoma, have been described in the literature, but relatively few cases of triple hit lymphoma have been reported. Additionally, without chemotherapy, triple hit lymphomas are known to have a rapid clinical course and poor prognosis compared to double hit lymphomas. Here we present a case of MYC/BCL2/BCL6 triple hit lymphoma in a patient previously diagnosed with marginal B-cell lymphoma at stage IIA after biopsy of intra-abdominal lymph nodes status post one treatment with rituximab and bendamustine. Unfortunately, this patient had a rapid decline and presumed central nervous system (CNS) infiltration and passed away within 30 days of diagnosis.

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Trajkova, Sanja, Svetlana Krstevska-Balkanov, Gordana Petrusevska, Lidija Cevreska, Aleksandra Pivkova-Veljanovska, Marija Popova-Labacevska, Nevenka Ridova, Simona Stojanovska, and Irina Panovska-Stavridis. "Prognostic impact of immunophenotyping of diffuse large B-cell lymphoma - a single-centre experience." Macedonian Pharmaceutical Bulletin 67, no. 1 (2021): 43–54. http://dx.doi.org/10.33320/10.33320/maced.pharm.bull.2021.67.01.005.

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The concept generated by biological expression profile divided patients with diffuse large B-cell lymphoma (DLBCL) into two subtypes. This concept has been presented in the recent editions of WHO classification and became a prognostic tool. Aim of the study was introduction of new three-marker model for immunohistochemical and prognostic subclasification of patients with DLBCL. Our retrospective study enrolled 200 adult patients with DLBCL diagnosed and treated in the period between January 2013 to January 2021. They were all treated with chemoimmunotherapy with R+/-CHOP regimen and the median follow-up of the patients was 48 months. We analysed the biopsy samples immunohistochemically with the markers of germinal (BCL6) and post-germinal centre (MUM1), and the marker of apoptosis (BCL2). Using the immunohistochemical three-marker model, which consisted of BCL-2, BCL-6, and MUM1, we distributed the patients with DLBCL into 2 subgroups: germinal centre – like (GCL) and activated centre-like lymphoma (ACL). The GCL and ACL patients were comparable regarding age, gender and all other already established prognostic parameters. Patients with GCL had overall survival of 140 months, and patients with ACL had overall survival of 88 months. ACL patients with BCL2 expression had a shorter survival compared to ACL patients without BCL2 expression. The difference in survival was statistically significant for p=0.01914. The study introduced the new three-marker model for immunohistochemical subclasification of patients with DLBCL treated with immunochemotherapy. Apoptotic marker BCL2 is a strong survival predictor. In the present study, we confirmed the prognostic importance of BCL2 protein expression, which showed a predictive capacity in ACL. Keywords: DLBCL, three - marker model, immunohistochemical, BCL2

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Arun Kumar, Sumukh, Rahul Mishra, Sarat Chandra Malempati, and Poorva Bindal. "Primary cardiac large B cell lymphoma." BMJ Case Reports 16, no. 12 (December 2023): e256167. http://dx.doi.org/10.1136/bcr-2023-256167.

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A female patient in her mid-60s presented with progressive shortness of breath, pleuritic chest pain and bilateral leg swelling for 1 week. Initial diagnostic workup revealed pericardial effusion, and a localised pericardial tubular mass on CT chest. Pericardial fluid analysis showed elevated white cells, with predominance of medium-large sized atypical lymphoid cells. Atypical lymphocytes stained positive for CD79a, CD10, PAX-5, BCL-2 and BCL6. Fluorescence in situ hybridisation testing demonstrated MYC and BCL6 rearrangements without BCL2 gene rearrangement. The overall morphological, immunohistochemical and cytogenetic findings supported a diagnosis of high-grade B cell lymphoma with MYC and BCL6 rearrangements. After extensive staging workup, localised disease involving the pericardium with a diagnosis of primary cardiac large B cell lymphoma was established. She was treated with dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab chemotherapy. Rituximab was discontinued owing to largely absent CD20 expression. Interim positron emission tomography-CT after three cycles revealed a complete response, and the patient completed six cycles of therapy.

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Kawakami, Keiki, Setsuko Miyanishi, Takashi Sonoki, Shigeo Nakamura, Kenichi Nomura, Kenichi Nomura, Tetsuya Murata, Shigenori Kadowaki, Shigenori Kadowaki, and Ikuo Miura. "Case of B-Cell Lymphoma with Rearrangement of the BCL1, BCL2, BCL6, and c-MYC Genes." International Journal of Hematology 79, no. 5 (June 1, 2004): 474–79. http://dx.doi.org/10.1532/ijh97.03105.

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Amallraja, Anu, Gunes Gundem, Dylan Domenico, Juan E. Arango Ossa, Umut Aypar, Jeeyeon Baik, Michael Kluk, et al. "Genomic Characterization and Classification of BCL6 Rearranged Follicular Lymphomas." Blood 144, Supplement 1 (November 5, 2024): 1589. https://doi.org/10.1182/blood-2024-203770.

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Introduction Follicular lymphoma (FL) is the most common type of indolent non-Hodgkin's lymphoma with BCL6 rearrangements (BCL6-R) observed in 5-15% of cases. BCL6-R FL frequently exhibit concurrent canonical BCL2 rearrangements (BCL2-R). However, a subset presents with BCL6-R exclusively and shares biological features with the recently described genomic subgroup of diffuse large B-cell lymphoma, BN2, characterized by BCL6-R and a mutational profile suggestive of marginal zone lymphoma (MZL) (Schmitz 2018). In this study, we analyzed 14 BCL6-R FL samples to study the mechanisms generating the BCL6 and BCL2 rearrangements. Methods WGS was performed in 14 FL tumors determined to be BCL6 rearranged by clinical cytogenetics (median coverage 71x) and matched germline controls (median coverage 41x). Bioinformatics analysis was performed to align sequencing reads, call somatic variants - mutations, indels, rearrangements, and detect mutational signatures and clonal structures as described (Shukla, Levine, Gundem 2022). Kataegis was detected using {katdetectR} (Hazelaar 2023) and Ig loci were characterized by IgCaller (Nadeu 2020). The LymphGen classification algorithm was run on the NCI website (Wright 2020). Results and Discussion Genome-wide mutation calling identified a median of 16.7k SNVs, 10.7k Indels and 0.2k SVs per sample. Driver events were detected in all 14 samples with 93% of samples having at least 5 events. Mutations in epigenetic modifier genes like KMT2D, CREBBP, ARID1A and deletions in the CDKN2A/CDKN2B/MTAP locus were the most frequent. Non-canonical (SBS9) and canonical (SBS84) AID mutational signatures were detected in all samples. Recurrent driver rearrangements were identified in BCL6 (n = 14) and BCL2 (n = 10). BCL2-R (n = 8) were found to be predominantly created by RAG mediated aberrant VDJ recombination, whereas most BCL6-R (n = 11) were found to be generated through AID mediated aberrant class switch recombination or somatic hypermutation. These results suggest that in cases with concurrent BCL2-R and BCL6-R, BCL2-R occurred early in the B-cell ontogeny within the bone marrow whereas BCL6-R occurred later within the germinal center. Most BCL6-R associated with a BCL2-R involved non-Ig partners (n = 8), whereas exclusive BCL6-R were partnered with IgH. The LymphGen algorithm classified samples into EZB (n = 11, 78.57%), BN2 (n = 2, 14.28%), EZB/A53 (n = 1, 7.14%). Two cases with exclusive BCL6-R showed mutational profiles similar to MZL, including mutations in the NOTCH pathway, and were classified as BN2. Conclusions WGS-based comprehensive genomic profiling of BCL6-R FL revealed that BCL6-R are generated by AID mediated CSR or somatic hypermutation, regardless of whether they were the primary driver (BCL6-R only) or secondary to existing BCL2-R. Exclusive BCL6-R were associated IgH gene region enhancers and are likely to be pathogenic drivers associated with overexpression of the BCL6 protein, whereas BCL6-R with concurrent BCL2-R revealed different partners and might represent passenger events rather than true oncogenic drivers. Cases with BCL6-R only exhibit MZL like mutations and may represent a unique subset of B-cell lymphomas biologically closer to MZL than to FL.

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Haralambieva, Eugenia, Evert-jan Boerma, Gustaaf van Imhoff, Stefano Rosati, Ed Schuuring, Hans-Konrad Mueller-Hermelink, Philip M. Kluin, and German Ott. "The Grey Zone between Burkitt and Diffuse Large B Cell Lymphomas: Impact of Chromosomal Breakponts at Myc and Other Loci." Blood 104, no. 11 (November 16, 2004): 2275. http://dx.doi.org/10.1182/blood.v104.11.2275.2275.

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Abstract A prompt distinction of Burkitt lymphoma (BL) versus diffuse large B cell lymphoma (DLBCL) has important clinical implications. We analyzed 74 adult grey zone lymphomas (BL/DLBCL) and 10 reference pediatric BL using immunohistochemistry for Ki-67, CD10, bcl2 and bcl6, and Fluorescence In Situ Hybridization (FISH) for MYC, BCL2 and BCL6 breakpoints. Four hematopathologists reached a final (consensus) diagnosis independently in 80% of the reference BL, 24% of the test BL and 69% of the DLBCL. A MYC breakpoint was detected in all reference BL, 95% of the test BL and 35% of the DLBCL. BCL2 and BCL6 breakpoints were infrequent in BL (5 and 6%) and DLBCL (13% and 16%). Three BL and 5 DLBCL contained double breakpoints. A phenotypic shift to BL in the DLBCL group was indicated by the expression of CD10 and bcl6 in 67% and 91% of the cases, respectively. One third of all lymphomas showed a classical genotype and expression pattern of BL (MYC breakpoint+, Ki-67>90%, CD10+, bcl6+, bcl2-) but only 63% of these cases were classified as BL. Our data indicate that a subgroup of DLBCL shares markers with BL, which is probably due to an overlapping histogenesis of both tumors. Value of immunohistochemistry and additional FISH for BCL2 and BCL6 breakpoints to reach the consensus diagnosis in 38 MYC breakpoint carrying cases of adult grey zone BL / DLBCL lymphomas BCL2 and BCL6 breakpoint no restriction not present no restriction not present 38 / 74 cases carried a MYC/8q24 breakpoint phenotype no restriction no restriction Ki67>90%, CD10+, bcl6+, bcl2- Ki67>90%, CD10+, bcl6+, bcl2- N 38 30 24 22 Burkitt (%) 20 (53) 17 (57) 15 (63) 15 (68) DLBCL (%) 18 (47) 13 (43) 9 (37) 7 (32)

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Ci, Weimin, Jose M. Polo, Leandro Cerchietti, Rita Shaknovich, Ling Wang, Shao Ning Yang, Kenny Ye, et al. "The BCL6 transcriptional program features repression of multiple oncogenes in primary B cells and is deregulated in DLBCL." Blood 113, no. 22 (May 28, 2009): 5536–48. http://dx.doi.org/10.1182/blood-2008-12-193037.

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The BCL6 transcriptional repressor is required for development of germinal center (GC) B cells and when expressed constitutively causes diffuse large B-cell lymphomas (DLBCLs). We examined genome-wide BCL6 promoter binding in GC B cells versus DLBCLs to better understand its function in these settings. BCL6 bound to both distinct and common sets of functionally related gene in normal GC cells versus DLBCL cells. Certain BCL6 target genes were preferentially repressed in GC B cells, but not DLBCL cells. Several such genes have prominent oncogenic functions, such as BCL2, MYC, BMI1, EIF4E, JUNB, and CCND1. BCL6 and BCL2 expression was negatively correlated in primary DLBCLs except in the presence of BCL2 translocations. The specific BCL6 inhibitor retro-inverso BCL6 peptidomimetic inhibitor-induced expression of BCL2 and other oncogenes, consistent with direct repression effects by BCL6. These data are consistent with a model whereby BCL6 can directly silence oncogenes in GC B cells and counterbalance its own tumorigenic potential. Finally, a BCL6 consensus sequence and binding sites for other physiologically relevant transcription factors were highly enriched among target genes and distributed in a pathway-dependent manner, suggesting that BCL6 forms specific regulatory circuits with other B-cell transcriptional factors.

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Biehl, Holger, Jeremy C. Creasey, David M. Smith, Richard P. Tuckett, Karl R. Yoxall, Helmut Baumgartel, Hans W. Jochims, and Ulriche Rockland. "Vacuum UV fluorescence excitation spectroscopy of BCl3. Electronic spectroscopy of BCl2, BCl2 + and BCl3 +." Journal of the Chemical Society, Faraday Transactions 91, no. 18 (1995): 3073. http://dx.doi.org/10.1039/ft9959103073.

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Dierlamm, J., S. Pittaluga, I. Wlodarska, M. Stul, J. Thomas, M. Boogaerts, L. Michaux, A. Driessen, C. Mecucci, and JJ Cassiman. "Marginal zone B-cell lymphomas of different sites share similar cytogenetic and morphologic features [see comments]." Blood 87, no. 1 (January 1, 1996): 299–307. http://dx.doi.org/10.1182/blood.v87.1.299.299.

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Abstract Clinical, histologic, cytogenetic, and molecular genetic data of 31 patients with extranodal, nodal, and splenic marginal zone B-cell lymphoma (MZBCL) are presented. Despite these variable clinical manifestations, a similar spectrum of morphologic features as well as distinctive immunophenotypic findings were noted. In all cases, a monotypic B-cell proliferation consistently negative for CD5, CD10, and CD23 was found expanding the marginal zone of the B follicle with and without colonization of the follicle centers. Clonal chromosomal abnormalities were detected in 23 of the 31 patients. Recurrent aberrations included whole or partial trisomy 3 (18 cases), trisomy 18 (9 cases), and structural rearrangements of chromosome 1 with breakpoints in 1q21 (9 cases) or 1p34 (6 cases), all of which were seen in extranodal, nodal, as well as splenic MZBCL. Abnormalities of the additional chromosome 3, such as +del(3)(p13),+i(3)(q10), or structural changes involving the distal part of the long arm, were evident in 9 of the 18 cases. All recurrent abnormalities were found in MZBCL more frequently than in other histologic entities of B-cell non-Hodgkin's lymphoma (B-NHL). None of the known lymphoma-associated chromosomal changes or rearrangements of the BCL1, BCL2, BCL3, BCL6, and CMYC genes were detected. We conclude that MZBCL represent a distinct entity of B- NHL with characteristic morphologic and immunophenotypic features and particular chromosomal abnormalities, and that a close histogenetic relationship between extranodal, nodal, and splenic MZBCL is likely, although the clinical presentation may vary.

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Dierlamm, J., S. Pittaluga, I. Wlodarska, M. Stul, J. Thomas, M. Boogaerts, L. Michaux, A. Driessen, C. Mecucci, and JJ Cassiman. "Marginal zone B-cell lymphomas of different sites share similar cytogenetic and morphologic features [see comments]." Blood 87, no. 1 (January 1, 1996): 299–307. http://dx.doi.org/10.1182/blood.v87.1.299.bloodjournal871299.

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Clinical, histologic, cytogenetic, and molecular genetic data of 31 patients with extranodal, nodal, and splenic marginal zone B-cell lymphoma (MZBCL) are presented. Despite these variable clinical manifestations, a similar spectrum of morphologic features as well as distinctive immunophenotypic findings were noted. In all cases, a monotypic B-cell proliferation consistently negative for CD5, CD10, and CD23 was found expanding the marginal zone of the B follicle with and without colonization of the follicle centers. Clonal chromosomal abnormalities were detected in 23 of the 31 patients. Recurrent aberrations included whole or partial trisomy 3 (18 cases), trisomy 18 (9 cases), and structural rearrangements of chromosome 1 with breakpoints in 1q21 (9 cases) or 1p34 (6 cases), all of which were seen in extranodal, nodal, as well as splenic MZBCL. Abnormalities of the additional chromosome 3, such as +del(3)(p13),+i(3)(q10), or structural changes involving the distal part of the long arm, were evident in 9 of the 18 cases. All recurrent abnormalities were found in MZBCL more frequently than in other histologic entities of B-cell non-Hodgkin's lymphoma (B-NHL). None of the known lymphoma-associated chromosomal changes or rearrangements of the BCL1, BCL2, BCL3, BCL6, and CMYC genes were detected. We conclude that MZBCL represent a distinct entity of B- NHL with characteristic morphologic and immunophenotypic features and particular chromosomal abnormalities, and that a close histogenetic relationship between extranodal, nodal, and splenic MZBCL is likely, although the clinical presentation may vary.

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Tsai, Cheng-Chih, Yung-Cheng Su, Oluwaseun Adebayo Bamodu, Bo-Jung Chen, Wen-Chiuan Tsai, Wei-Hong Cheng, Chii-Hong Lee, et al. "High-Grade B-Cell Lymphoma (HGBL) with MYC and BCL2 and/or BCL6 Rearrangements Is Predominantly BCL6-Rearranged and BCL6-Expressing in Taiwan." Cancers 13, no. 7 (March 31, 2021): 1620. http://dx.doi.org/10.3390/cancers13071620.

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This study investigated the epidemiological and clinical peculiarities of BCL2 and BCL6 rearrangement in patients with high grade B-cell lymphoma (HGBL) from Taiwan, compared with data from Western countries. Two hundred and eighty-two DLBCL cases from Taipei Medical University-affiliated hospitals (n = 179) and Tri-Service General Hospital (n = 103) were enrolled for this study. From the 282, 47 (16.7%) had MYC translocation; 24 of these harbored concurrent BCL2 and/or BCL6 translocation (double-hit, DH or triple-hit, TH). Twelve DH-HGBL cases had simultaneous MYC and BCL6 translocations, 8 harbored MYC and BCL2 rearrangement, while the remaining 4 patients exhibited TH. Together, 66.7% of DH/TH-HGBL patients were BCL6 rearrangement positive. Among these BCL6-rearranged DH/TH-HGBL patients, only 6 (37.5%) overexpressed MYC and BCL6 proteins simultaneously, indicating that MYC-BCL6 co-overexpression may not be plausible surrogate biomarker for screening BCL6-rearranged DH-HGBL. By the end of year 5, all patients with TH-HGBL, BCL2 DH-HGBL and all but one BCL6 DH-HGBL cases had expired or were lost to follow-up. Progression-free survival (PFS) was longer for the non-DH/TH-HGBL group compared with the DH/TH-HGBL group. While the patients with BCL2 DH-HGBL were lost to follow-up by day 800, their remaining TH-HGBL and BCL6 DH-HGBL peers exhibited very poor PFS, regardless of age strata. More so, patients with BCL6 rearrangement were 5.5-fold more likely associated with extranodal involvement compared with their BCL2-rearranged peers. Moreover, ~60.0% of the BCL6-rearranged DH-HGBL cases were non-GCB, suggesting that including screening for BCL6 rearrangement in patients with the non-GCB phenotype may aid medical decision-making and therapeutic strategy. Contrary to contemporary data from western countries, 2 in every 3 patients with DH/TH-HGBL in Taiwan harbor BCL6 rearrangement. Consistent with present findings, we recommend mandatory screening for BCL6 rearrangement in patients with aggressive HGBL in Taiwan.

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Horn, Heike, Marita Ziepert, Thomas F. E. Barth, Heinz-Wolfram Bernd, Martin Wartenberg, Alfred C. Feller, Wolfram Klapper, et al. "The Prognostic Impact Of Gene Rearrangements and Protein Expression Of MYC, BCL2 and BCL6 In Young High-Risk Patients With DLBCL." Blood 122, no. 21 (November 15, 2013): 4262. http://dx.doi.org/10.1182/blood.v122.21.4262.4262.

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Abstract Purpose A number of retrospective analyses have looked into the prognostic implication of MYC, BCL2 and BCL6 rearrangements and protein expression for MYC, BCL2 and BCL6 in patients with diffuse large B-cell lymphoma (DLBCL). Many of these studies suffer from small patient cohorts and differing or unknown treatment strategies (with or without Rituximab) administered to patients under study. Furthermore, the median age of these patients was relatively high. We for the first time report on the prognostic consequences of MYC, BCL2 and BCL6 alterations in younger (18-60 years) high-risk patients (aaIPI 2 or 3) with DLBCL. Patients and Methods The MegaCHOEP study (Schmitz et al. Lancet Oncology 2012: 13, 1250) randomized patients to 8xCHOEP-14 or sequential high-dose therapy supported by repeated infusions of autologous stem cells. Both treatment arms included 6 infusions of R (375 mg/ sqm). The median patient age was 48 years, and 27% of patients scored an aaIPI of 3. Paraffin-embedded tumor samples from 112 de novo DLBCL were investigated using immunohistochemistry for MYC, BCL2, and BCL6, and fluorescence in-situ hybridisation (FISH) to detect breaks of MYC, BCL2 and BCL6. Results Rearrangements of MYC, BCL2 and BCL6 were detected in 13.6%, 20.7% and 30.9% of DLBCL, respectively. A double or triple hit constellation occurred in 10.8%. Presence of BCL2 breaks (RR=4.7, 95% CI: 1.8-12.2) and MYC breaks (RR=2.4, 95% CI: 0.8-7.5), but not of BCL6 breaks were associated with inferior overall survival in univariate and multivariate analyses adjusted for aaIPI and treatment arm. Protein overexpression of MYC ≥30% (RR=2.4, 95% CI: 0.9-6.5), but not BCL2 (≥60%) or BCL6 (≥30%) indicated inferior overall survival. BCL2 overexpression was associated with inferior EFS (RR=2.2, 95% CI: 0.9-5.5) and PFS (RR=2.8, 95% CI: 1.0-8.2). If the same cutpoint for BCL2 used for a similar analysis in elderly patients treated on the RICOVER-60 trial (Horn et al. Blood 2013) was applied, no differences in EFS or PFS were observed. Conclusion Rearrangements of MYC and BCL2 seem to be relevant prognostic factors also in young high-risk patients. The frequencies of MYC and BCL2 rearrangements are not substantially higher than reported for other, mostly elderly patient groups carrying IPI scores from 0 - 5; it seems unlikely, therefore, that the rearrangements described here (completely) explain the poor prognosis of young, high-risk patients. The prognostic role of BCL2, BCL6, and MYC as well as other biological risk factors must be validated in independent data sets. Disclosures: No relevant conflicts of interest to declare.

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Ma, Zhiping, Jing Niu, Yanzhen Cao, Xuelian Pang, Wenli Cui, Wei Zhang, and Xinxia Li. "Clinical significance of ‘double-hit’ and ‘double-expression’ lymphomas." Journal of Clinical Pathology 73, no. 3 (October 15, 2019): 126–38. http://dx.doi.org/10.1136/jclinpath-2019-206199.

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Background‘Double-hit’ lymphoma (DHL) and ‘double-expression’ lymphoma (DEL) involving gene rearrangement and protein expression of MYC and BCL2/BCL6 have recently become the most commonly used terms to describe the poor prognostic types of diffuse large B-cell lymphoma (DLBCL). However, the clinical and pathological spectra of these rare entities have not been well defined. The aim of this study was to determine the frequency of DHL and DEL in DLBCL and their prognostic impacts in the era of cyclophosphamide, doxorubicin, vincristine and prednisone plus rituximab therapy.MethodsThe data and tissues from 98 patients diagnosed with DLBCL were used in this study. Formalin-fixed and paraffin-embedded tissues were constructed for immunohistochemistry (IHC) and interphase fluorescene in situ hybridisation (FISH) analysis for MYC, BCL6 and BCL2 rearrangements.ResultsThere were 14 cases (14.29%, 14/98) and 34 cases (34.70%, 34/98) of lymphomas with the DHL and DEL of MYC and BCL2/BCL6, respectively. DLBCL patients with MYC/BCL2 rearrangements more frequently had bone marrow involvement (p=0.002), and their tumours were commonly of the germinal centre B cell (GCB) subtype. Patients with MYC+/BCL2 +coexpression were more often assessed using the International Prognostic Index (IPI), (Performance Status) PS score and bone marrow involvement. Patients with MYC+/BCL6 +coexpression were associated with their IPI values, Eastern Cooperative Oncology Group scores and occurrence of B symptoms. Their lymphomas were more often of the non-GCB subtype (p=0.010). Multivariate analysis showed that IPI, bone marrow involvement, rearrangements of BCL2, BCL6 and MYC, expression concurrent with rearrangements and coexpression were all significantly associated with overall survival and progression-free survival, with the exception of MYC+/BCL6 +coexpression.ConclusionsMYC/BCL2 DHL, MYC/BCL6 DHL and MYC/BCL2 DEL are an aggressive B cell lymphoma and patients have a poor prognosis. IPI and bone marrow involvement were independent prognostic factors for DHL and DEL. BCL2, BCL6 and MYC rearrangements translocation, expression concurrent rearrangements and coexpression were were independent prognostic factors for survival.Potential implicationsThe present study analysed the genomic alterations and protein expression levels of MYC, BCL2 and BCL6 using FISH and IHC in Chinese patients with DLBCL.We assessed the frequency, clinicopathological features and the prognostic impacts of DHL and DEL in a cohort of de novo DLBCL patients and evaluated the role of each genetic translocation separately and in combination in order to provide reliable conclusions and practical recommendations for diagnostic workups and prognostic predictions.

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Vallespi, Teresa, Margarita Ortega, Anny Jaramillo, Laura Lopez-Andreoni, Noemi Martínez-Morgado, Carmen Sánchez, and Francesc Bosch. "T(8;22)(q24;q11) In a Context of Complex Karyotype In Two Patients with B-Cell Lymphoma with Features Intermediate Between Burkitt Lymphoma and Diffuse Large B Cell Lymphoma B (LB/LDCGB)." Blood 116, no. 21 (November 19, 2010): 5093. http://dx.doi.org/10.1182/blood.v116.21.5093.5093.

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Abstract Abstract 5093 Background: In some cases, it is difficult to distinguish between the diagnosis of Burkitt lymphoma (LB) and Diffuse Large Cell Lymphoma B (DLCL-B) with MYC gene rearrangement. The WHO classification distinguishes three clinical entities: LB, LB/DLCL-B, DLCL-B on the basis of morphology, immunophenotype and genetic characteristics of malignant cells. The MYC gene is often rearranged with the gene that encodes the heavy chains of immunoglobulins (IgG 14q32) and, less frequently, with the gene that encodes the light chains kappa (2p12) or lambda (22q11). Objective: Describe clinical and biological characteristics of two cases of lymphoma with variant t(8;22)(q24;q11) in a complex karyotype diagnosed BL/DLCL-B according to the WHO classification. Methods and Patients: The cytogenetic study was made in the bone marrow (aspirate or biopsy). Leukocytes were incubated during 24h in RPMI without mitogens. Rearrangements of C-MYC, BCL-2, BCL-6 and IGH were studied for FISH techniques. The results were expressed according to ISCN 2009. Case 1: A man of 46 years who was admitted with symptoms of spinal cord compression with fever and weight loss. During admission were detected anti-HIV antibodies. In the biopsy were observed large cells with irregular nuclei, with clefts and some multilobulated. Imunohistochemistry: CD10 +, CD20 +, CD79 +, bcl2 + and BCL6 +. The Ki67/MIB1 was 95%. Cytogenetic study of bone cylinder showed a complex karyotype: 49, XY, +1, del (1) (p22), der (2), der (3), +7, t (8;22)(q24;q11), +10, del(10)(q24q26)x2 [3]. The FISH study demonstrated the rearrangement of C-MYC and the absence of BCL2 and BCL6 rearrangement. Case 2: A man of 67 year old was admitted for epigastric pain, nausea, vomiting and weight loss. The aspirated cells were of medium and large size, irregularly shaped nuclei, some creases and other poly-lobed with prominent nucleoli. Was detected by immunohistochemistry positivity: CD10, CD20, CD79 and BCL6 Ki67/MIB1 presented a 90%. Cytogenetic study of the bone marrow showed a complex karyotype: 49, XY, t(1;11)(q21;p13),+7, t(7;13) q32;q12), t (8;22)(q24;q11),+12,+19[40]. The FISH study demonstrated presence of the rearrangement of C-MYC and BCL2 and BCL6 rearrangement absence. Conclusions: - Both cases are representative of the clinical entity BL// DLCL-B recently recognized by the WHO: anisocitosicas cells with a nucleus of irregular or poly-lobed, with Ki67/MIB1 <90% and C-MYC rearranged with a complex karyotype. - Both cases showed the t(8;22)(q24;q11) rare variant of Burkitt lymphoma and a trisomy 7, trisomy usually observed in DLCL-B. Disclosures: No relevant conflicts of interest to declare.

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Abramson, Jeremy S., Jeffrey A. Barnes, Yang Feng, Tak Takvorian, Donna S. Neuberg, Ephraim P. Hochberg, and Aliyah R. Sohani. "Double Hit Lymphomas: Evaluation of Prognostic Factors and Impact of Therapy." Blood 120, no. 21 (November 16, 2012): 1619. http://dx.doi.org/10.1182/blood.v120.21.1619.1619.

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Abstract Abstract 1619 Introduction: Double-hit lymphomas (DHL) harboring rearrangements or additional copies of MYC and BCL2 or less commonly BCL6 have been associated with a poor prognosis, but data remains limited. We conducted a retrospective analysis of DHLs to evaluate for factors associated with an improved prognosis. Methods: We identified DHL cases diagnosed 2004–2011. Cases were included if they had rearrangements or extra copies of MYC as well as BCL2 or BCL6, or both. Overall survival (OS) was defined as the time from biopsy to death. Progression-free survival (PFS) was defined as time from biopsy to progression or death without progression. OS and PFS curves were obtained using the Kaplan-Meier method with 90% confidence intervals calculated using Greenwood's formula. Univariate analysis for risk factors was conducted with the log-rank test using a two-sided significance level of 0.05. Stepwise multivariable Cox regression analyses of PFS and OS were utilized to identify significant prognostic factors. Results: Thirty-four DHL patients were included in the analysis. Twenty-eight patients (82%) had rearrangements of both MYC and BCL2, one of whom also had a BCL6 translocation. Two patients had rearrangements of MYC and BCL6. One patient each had rearrangement of MYC with 8 copies of BCL2, rearrangement of BCL2 with 3 copies of MYC, rearrangement of BCL2 with 4 copies of MYC, and rearrangement of BCL6 with 4 copies of MYC. Based on the WHO classification, 35% had DLBCL morphology, while 65% had B-cell lymphoma unclassifiable with intermediate features between DLBCL and BL (BCLU). Median Ki67 was 90% (range 25–100%). The median age was 63 (range 32–86 years), and gender was evenly divided. Prior follicular lymphoma was present in 10 patients (29%). Twenty-nine patients (85%) had advanced stage disease, with 27 (79%) presenting at stage IV and 2 at stage III. Five patients (15%) had limited-stage disease. Extranodal disease was present in 26 (77%), including 6 patients with CNS disease, 9 with leukemic disease, and 15 with marrow disease. Eighteen patients (53%) had 2 or more extranodal sites involved at diagnosis. Performance status was 0–1 in the majority of patients (88%). LDH was elevated in 30 patients (88%). The mean LDH was 1388 (range 151 – 10840). The IPI score was 0–1 in 15%, 2–3 in 35% and 4–5 in 50%. Fifteen (44%) patients were treated with R-CHOP, 6 (18%) with R-CODOX-M/IVAC, 12 (35%) with R-EPOCH, and 1 patient with best supportive care. Two patients underwent consolidative SCT in first remission following R-EPOCH; 1 patient underwent auto SCT, another patient underwent auto SCT followed by reduced-intensity allo SCT on a clinical trial. Complete response were achieved in 22 (64%), partial response in 2 (6%), and progressive disease in 10 (29%). At a median of 25 months, 13 patients (38%) remain alive and free from progression. The median PFS is 8 months (90% CI [5, 21]) and the median OS is 11 months (90% CI [7–37]). Univariate analysis for PFS identified adverse risk factors of elevated LDH, IPI score 4–5, extranodal disease, marrow involvement, and leukemic phase. Univariate analysis for OS identified adverse risk factors to be BCLU morphology, elevated LDH, IPI score 4–5, extranodal disease, and leukemic phase. For both PFS and OS, univariate analysis demonstrated a more favorable outcome in patients with DLBCL morphology, and for those treated with R-EPOCH. Median PFS and OS for R-EPOCH patients were 21 and 34 months, respectively, compared to 6 and 8 months for R-CHOP, and 6 and 7 months for R-CODOX-M/IVAC. Multivariable analysis for PFS identified presence of extranodal disease (HR 19, 90%CI[3.3–112]) and BCLU morphology (HR 5.2, 90%CI[1.9–14]) as adverse predictors of outcome. Multivariable analysis for OS identified leukemic disease as an adverse risk factor (HR 6.6, 90%CI[2.4–18]) and R-EPOCH therapy as a protective factor (HR 0.3, 90%CI[0.1–0.9]). Conclusions: DHLs are highly aggressive lymphomas with a poor overall prognosis. A subset, however, will present with more favorable characteristics predicting a higher rate of cure, including DLBCL morphology, normal LDH, absence of extranodal disease and IPI score of 0–2. R-EPOCH may perform better than other regimens, though this requires prospective validation in larger series. Disclosures: Abramson: Genentech: Consultancy. Hochberg:Genentech: Consultancy; Biogen-Idec: Consultancy.

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Worrillow, Lisa J., Rob Newton, and Andrew S. Jack. "The Pattern of BCL6 Intron 1 Mutations in Healthy Individuals with BCL2;IgH Is Similar to That Seen in Lymphomas." Blood 112, no. 11 (November 16, 2008): 3800. http://dx.doi.org/10.1182/blood.v112.11.3800.3800.

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Abstract Mutational clustering in intron 1 of BCL6, and BCL2;IgH translocation are commonly found in peripheral lymphocytes from healthy individuals. These abnormalities, most likely the consequence of mistargeted rearrangement and somatic hypermutation of the immunoglobulin locus, are also associated with lymphoma. However, the relevance of these findings to disease pathogenesis remains unclear. Given that deregulated BCL2 expression is likely to promote cell survival, we hypothesized that the frequency of BCL6 intron 1 mutations would increase in germinal centre B-cells carrying BCL2;IgH. We also investigated whether the frequency of both abnormalities was altered by chronic immune stimulation using rheumatoid arthritis (RA) as a model. Initially, BCL2;IgH positive cases were identified in healthy controls (n=256) and RA cases (n=132) by real-time quantitative PCR. Frequency (16%) and quantity (2 copies/104 B-cells) of BCL2;IgH was equal in pre-rituximab RA cases and controls, with no significant differences associated with age or gender. As expected, few post-treatment cases carried detectable BCL2;IgH. We then analyzed BCL6 intron 1 somatic mutations in matched RA cases and controls with (n=10) or without (n=10) detectable BCL2;IgH using a cloning and sequencing strategy (10 colonies sequenced/case or control). Although mutation frequency was similar irrespective of RA or translocation status, the percentage of colonies carrying at least one mutation was slightly higher (but not significantly) in those with detectable BCL2;IgH (76%) than in those without (67%). This indicates that BCL2 translocation plays a minimal role in the ability of germinal centre B-cells to tolerate mutations accumulating in BCL6, and possibly other proto-oncogenes mistargeted by somatic hypermutation. As base changes are preferentially introduced at motifs recognised by activation-induced deaminase (RGYW/WRCY) and polymerase η (A/T) during somatic hypermutation, we determined the number of mutational events within these regions and found no significant differences between any of the groups investigated. This infers that the rate of somatic hypermutation remains consistent irrespective of chronic immune stimulation or BCL2 translocation. Given that the pattern of mutations in BCL6 intron 1 has been reported to vary between sub-types of B-cell lymphoma, we searched for mutational clusters within the cloned BCL6 sequence and found obvious differences between groups with detectable BCL2;IgH compared to those without. In particular, a mutational hotspot was evident at 500 to 520 bases, a region of BCL6 intron 1 also targeted in B-cell lymphoma. It is possible that this hotspot lies within a site which may modify BCL6 expression within the germinal centre altering susceptibility to additional aberrant genetic events such as BCL2 translocation. However, as BCL2;IgH and BCL6 mutations are likely to co-exist within a healthy population these changes may represent a normal B-cell population with a slight tendency to become increasingly unstable. Overall, we have shown that mutations in BCL6 and BCL2;IgH rearrangements are common in a healthy population and do not appear to be affected by chronic immune stimulation. However, this study has identified a group of patients with BCL2;IgH rearrangements who have a pattern of BCL6 mutations similar to that observed in lymphoma. Further studies are required to determine whether these patients are potentially at risk of developing a lymphoid malignancy.

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Kramer, M. H. H., J. Hermans, E. Wijburg, K. Philippo, E. Geelen, J. H. J. M. van Krieken, D. de Jong, E. Maartense, E. Schuuring, and P. M. Kluin. "Clinical Relevance of BCL2, BCL6, and MYC Rearrangements in Diffuse Large B-Cell Lymphoma." Blood 92, no. 9 (November 1, 1998): 3152–62. http://dx.doi.org/10.1182/blood.v92.9.3152.

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Abstract Diffuse large B-cell lymphoma (DLCL) is characterized by a marked degree of morphologic and clinical heterogeneity. We studied 156 patients with de novo DLCL for rearrangements of the BCL2, BCL6, and MYC oncogenes by Southern blot analysis and BCL2 protein expression. We related these data to the primary site of presentation, disease stage, and other clinical risk factors. Structural alterations of BCL2, BCL6, and MYC were detected in 25 of 156, 36 of 116, and 10 of 151 patients, respectively. Three cases showed a combination of BCL2 and BCL6 rearrangements, and two cases had a combination of BCL6 and MYC rearrangements. BCL2 rearrangement was found more often in extensive (39%) and primary nodal (17%) lymphomas than in extranodal cases (4%) (P = .003). BCL2 rearrangement was present in none of 40 patients with stage I disease, but in 22% of patients with stage II to IV (P = .006). The presence of BCL2 rearrangements did not significantly affect overall survival (OS) or disease-free survival (DFS). In contrast, high BCL2 protein expression adversely affected both OS (P = .008) and DFS (P = .01). BCL2 protein expression was poorly correlated with BCL2 rearrangement: only 52% of BCL2-rearranged lymphomas and 37% of BCL2-unrearranged cases had high BCL2 protein expression. Rearrangement of BCL6 was found more often in patients with extranodal (36%) and extensive (39%) presentation versus primary nodal disease (28%). No significant correlation was found with disease stage, lymphadenopathy, or bone marrow involvement. DFS and OS were not influenced by BCL6 rearrangements. MYC rearrangements were found in 16% of primary extranodal lymphomas, versus 2% of primary nodal cases (P = .02). In particular, gastrointestinal (GI) lymphomas (5 of 18 cases, 28%) were affected by MYC rearrangements. The distinct biologic behavior of these extranodal lymphomas was reflected by a high complete remission (CR) rate: 7 of 10 patients with MYC rearrangement attained complete remission and 6 responders remained alive for more than 4 years, resulting in a trend for better DFS (P = .07). These data show the complex nature of molecular events in DLCL, which is a reflection of the morphologic and clinical heterogeneity of these lymphomas. However, thus far, these genetic rearrangements fail as prognostic markers. © 1998 by The American Society of Hematology.

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Kramer, M. H. H., J. Hermans, E. Wijburg, K. Philippo, E. Geelen, J. H. J. M. van Krieken, D. de Jong, E. Maartense, E. Schuuring, and P. M. Kluin. "Clinical Relevance of BCL2, BCL6, and MYC Rearrangements in Diffuse Large B-Cell Lymphoma." Blood 92, no. 9 (November 1, 1998): 3152–62. http://dx.doi.org/10.1182/blood.v92.9.3152.421a07_3152_3162.

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Diffuse large B-cell lymphoma (DLCL) is characterized by a marked degree of morphologic and clinical heterogeneity. We studied 156 patients with de novo DLCL for rearrangements of the BCL2, BCL6, and MYC oncogenes by Southern blot analysis and BCL2 protein expression. We related these data to the primary site of presentation, disease stage, and other clinical risk factors. Structural alterations of BCL2, BCL6, and MYC were detected in 25 of 156, 36 of 116, and 10 of 151 patients, respectively. Three cases showed a combination of BCL2 and BCL6 rearrangements, and two cases had a combination of BCL6 and MYC rearrangements. BCL2 rearrangement was found more often in extensive (39%) and primary nodal (17%) lymphomas than in extranodal cases (4%) (P = .003). BCL2 rearrangement was present in none of 40 patients with stage I disease, but in 22% of patients with stage II to IV (P = .006). The presence of BCL2 rearrangements did not significantly affect overall survival (OS) or disease-free survival (DFS). In contrast, high BCL2 protein expression adversely affected both OS (P = .008) and DFS (P = .01). BCL2 protein expression was poorly correlated with BCL2 rearrangement: only 52% of BCL2-rearranged lymphomas and 37% of BCL2-unrearranged cases had high BCL2 protein expression. Rearrangement of BCL6 was found more often in patients with extranodal (36%) and extensive (39%) presentation versus primary nodal disease (28%). No significant correlation was found with disease stage, lymphadenopathy, or bone marrow involvement. DFS and OS were not influenced by BCL6 rearrangements. MYC rearrangements were found in 16% of primary extranodal lymphomas, versus 2% of primary nodal cases (P = .02). In particular, gastrointestinal (GI) lymphomas (5 of 18 cases, 28%) were affected by MYC rearrangements. The distinct biologic behavior of these extranodal lymphomas was reflected by a high complete remission (CR) rate: 7 of 10 patients with MYC rearrangement attained complete remission and 6 responders remained alive for more than 4 years, resulting in a trend for better DFS (P = .07). These data show the complex nature of molecular events in DLCL, which is a reflection of the morphologic and clinical heterogeneity of these lymphomas. However, thus far, these genetic rearrangements fail as prognostic markers. © 1998 by The American Society of Hematology.

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Rossi, Davide, Valeria Spina, Clara Deambrogi, Marco Lucioni, Luca Arcaini, Gabrielle B. Rocque, Jeffrey T. Malik, et al. "TP53 Mutations, the Most Frequent Genetic Lesion in Richter Syndrome, Represent An Independent Predictor of Survival Post Transformation." Blood 114, no. 22 (November 20, 2009): 670. http://dx.doi.org/10.1182/blood.v114.22.670.670.

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Abstract Abstract 670 Richter syndrome (RS) represents the transformation of chronic lymphocytic leukemia (CLL) to aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL). Knowledge of the genetic lesions associated with RS is scant and represents the aim of this study. The study was based on 47 RS cases (all DLBCL). In 32 cases, paired CLL/RS samples were available (28 clonally related and 4 clonally unrelated). In 15 cases, the sole RS sample was analysed. According to CD10/BCL6/MUM1 immunohistochemistry expression pattern, 43/47 (91.5%) RS were classified as non-germinal center DLBCL. At diagnosis, 37.8% RS showed ECOG PS >1, 77.8% Binet stage B-C, 95.7% Ann Arbor stage III-IV, 44.4% B symptoms, 45.7% tumor size >5 cm, 32.6% involvement of >1 extranodal site, 66.7% LDH elevation, and 28.9% platelets <100 × 10e(9)/l. RS treatment included CHOP-like regimens in 71.1% cases, rituximab-based immunochemotherapy in 44.4%, and allogeneic stem cell transplant in 8.9%. Candidate genetic lesions were selected among those recurrently affecting: i) de novo DLBCL; and ii) CLL. Mutational analysis of the TNFAIP3/A20, CARD11, BLIMP1, and TP53 genes was performed by direct DNA sequencing. Probes used for FISH analysis were: i) LSI13, LSID13S319, CEP12, LSIp53, LSIATM, LSI IGH/BCL2, LSI BCL6, LSI IGH/c-MYC/CEP8, LSI N-MYC (Abbott); BCL3 split signal (Dako): iii) 6q21/alpha-satellite (Kreatech Biotechnology); iv) BAC clones 373L24-rel and 440P05-BCL11A. Clonal relationship between CLL and RS samples was assessed by immunoglobulin gene rearrangement analysis. Among gene mutations that are associated with de novo DLBCL, TP53 mutations (exons 4-8) were identified in 18/46 (39.1%) RS, and CARD11 mutations (exons 5-9) in 3/44 (6.8%). Neither TNFAIP3/A20 (exons 2-9) nor BLIMP1 (exons 2-4) mutations were identified in RS. Among chromosomal abnormalities that are associated with de novo DLBCL, c-MYC translocation was observed in 2/17 (11.8%) RS, c-MYC amplification in 2/17 (11.8%), BCL6 amplification in 2/17 (11.8%), REL amplification in 1/10 (10.0%), and BCL2 amplification in 1/17 (5.9%). Neither BCL6 translocation, nor BCL2 translocation or BLIMP1 deletion were observed in RS. Among chromosomal abnormalities that are associated with CLL, 17p13 deletion (TP53) was observed in 5/17 (29.4%) RS, 11q22-q23 deletion (ATM) in 5/17 (29.4%), +12 in 4/17 (23.5%), 13q14 deletion (MIR15A/16B) in 2/17 (11.8%), BCL11A amplification in 1/10 (10.0%), BCL3 amplification in 2/17 (11.8%), BCL3 translocation in 1/17 (5.9%), and N-MYC amplification in 1/17 (5.9%). Analysis of paired clonally related CLL/RS samples showed that TP53 mutations and CARD11 mutations are acquired at RS transformation. Chromosomal abnormalities acquired at RS transformation included TP53 deletion (3/10, 30.0%), c-MYC translocation (2/10, 20.0%), BCL3 amplification (2/10, 20.0%), c-MYC amplification (1/10, 10.0%), BCL6 amplification (1/10, 10.0%), BCL2 amplification (1/10, 10.0%), and ATM deletion (1/10, 10.0%). To date, the sole tool for predicting RS survival is represented by the RS score, that is based on clinical variables (Tsimberidou et al, J Clin Oncol 2006; 24:2343). The notion that TP53 status predict survival in both CLL (Zenz et al, Blood 2008; 112: 3322; Rossi et al, Clin Cancer Res 2009; 15: 995) and de novo DLBCL (Young et al, Blood 2008; 112: 3088) prompted investigation of the impact of TP53 mutations on survival post RS transformation. Survival post transformation was significantly longer in RS devoid of TP53 mutations (27.0 months) compared to RS with TP53 mutations (9.4 months) (p=.023) (Fig. 1). Other variables associated with RS survival were age (p<.001), ECOG PS (p<.001), tumor size (p=.001), B symptoms (p=.001), platelet count (p=.002), Binet stage (p=.001), Rai stage (p=.001), and IPI (p=.008). Treatment strategy did not affect RS survival. Multivariate analysis selected TP53 mutations (HR:2.34; p=.028) as an independent predictor of RS survival along with variables identified by the RS score, including ECOG PS (p=.008), tumor size (p<.001), and platelet count (p=.004) . The conclusions of our study are multifold: i) the genetic profile of RS differs from that of de novo DLBCL; ii) few lesions are shared by RS and de novo DLBCL, including CARD11 mutations, c-MYC translocation and REL amplification; iii) TP53 mutations are the most frequent genetic lesion in RS; iv) TP53 mutations are an independent prognostic factor in RS. Disclosures: No relevant conflicts of interest to declare.

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Sakruti, Susmita, Nabila Bennani, Swapna Thota, Rohan Garje, Adewale Fawole, Paul Elson, Abdo Haddad, Timothy Spiro, and Hamed Daw. "Diffuse Large B Cell Lymphoma: Role Of MYC, BCL2, BCL6 Protein Expressions and Translocations." Blood 122, no. 21 (November 15, 2013): 5055. http://dx.doi.org/10.1182/blood.v122.21.5055.5055.

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Abstract Introduction Diffuse large B cell lymphoma (DLBCL) accounts for approximately 30% of the non-Hodgkin’s lymphomas. However, DLBCL has heterogeneous clinical, histological, and molecular features. It has been identified that the clinical features and the treatment response vary with genetic and molecular features that affect disease aggressiveness. Gene rearrangements and more recently protein expressions involving MYC, BCL2 or BCL6 have been shown to have major prognostic implications. Lymphomas with recurrent chromosomal breakpoints activating multiple oncogenes, (one being MYC), are often referred to as “Double hit” lymphomas (DHL). Objectives The current study aims to identify patients with DLBCL for the presence of co-expression of proteins involving MYC with BCL2 and/or BCL6, corresponding translocations and their prognostic impact on response to therapy and overall survival. Methods Patients were retrospectively identified by reviewing tumor registries and pathology records at the Cleveland Clinic Health system for any of the diagnoses between January 1998 and December 2011: Burkitt-like lymphoma; Aggressive B-cell lymphoma NOS; “B-cell lymphoma unclassifiable with features intermediate between DLBCL and Burkitt's lymphoma”; High-grade B-cell lymphoma; Diffuse large B-cell lymphoma with aggressive features and Diffuse aggressive lymphoma NOS. Data collected included Clinical characteristics at the time of diagnosis, Immunohistochemistry, Cytogenetics, type of treatment received, response in terms of complete and partial remission and survival data. Patients aged < 18 years and with the diagnosis of low grade lymphoma and Burkitt's lymphoma were excluded from the study. Results Data from 65 patients diagnosed between June 2001 and February 2012 were available for analysis. Overall 52% of patients were male, median age at diagnosis was 69 yrs (range 36-89 yrs), and most had good ECOG performance status (82% ECOG 0, 1). Most patients had DLBCL (83%), and majority of the patients were stage 3 or 4 (63%). The most common sites of extranodal disease were bone marrow (26%), followed by Genitourinary (15%), and muscle (15%). The majority of patients were in the International Prognostic Index (IPI) poor risk group (53%) Positive MYC protein expression or translocation was found in 16 (24%) patients. 7 patients had DHL with 5 patients having MYC/BCL2 translocations, 1 patient-MYC/BCL6 and 1 patient with MYC/BCL2/ BCL6 ( Triple hit) translocations. 9 patients had MYC protein expression with or without translocation with co-expression of either BCL2 or BCL6 protein. 81% (53/65) of patients had BCL2 expression (14 had translocation), 65% (42/65) had BCL6 expression (7 had translocation), and 24% (16/65) had MYC protein expression (12 had translocation). 25 patients (38%) had a single protein expression; of which 14 patients had BCL2, 10 patients had BCL6 and 1 patient had MYC. 24 patients (37%) were positive for both BCL2 and BCL6 co-expression; of which 5 patients had positive translocations by FISH. 61 % (40/65) of the patients did not have FISH studies following immunohistochemistry. Overall 92% (60/65) of patients received systemic treatment, primarily RCHOP (73%). Only 54 patients had follow up data after treatment. 59% of the patients achieved a complete remission (CR), 22% had a best response of partial remission (PR), and 17% did not respond to treatment. 30 patients (54%) died with an estimated median overall survival of 58.9 months (26.6-127.7 months). As with response to chemotherapy, patients with a single protein expression with either BCL2 or BCL6, or co-expression with both BCL2/BCL6 had similar outcomes in terms of overall survival (79.9 vs 70.6 months) and CR (70% vs. 79%). Whereas, patients with protein expression/ translocation involving MYC tended to have poorer outcomes: 19% (3/16) had CR ( p=.0005) and estimated median survival of 11.5 months (p=.005). Conclusion Diffuse large B cell lymphomas involving co-expression of MYC protein with BCL2 or BCL6 have a significantly lower survival rate compared to the patients with single protein expression of BCL2 or BCL6 as well as co-expression of BCL2 and BCL6. In addition to obtaining cytogenetic studies, we emphasize the need to conduct prospective clinical trials which can aim at the optimal treatment strategies for this subset of DLBCL patients expressing the MYC proto-oncogene with BCL2 and/or BCL6 proteins. Disclosures: No relevant conflicts of interest to declare.

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Parkhi, Mayur, Debajyoti Chatterjee, Bishan Dass Radotra, Amanjit Bal, Budhi Singh Yadav, and Manjul Tripathi. "Double-hit and double-expressor primary central nervous system lymphoma: Experience from North India of an infrequent but aggressive variant." Surgical Neurology International 14 (May 12, 2023): 172. http://dx.doi.org/10.25259/sni_307_2023.

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Background: High-grade non-Hodgkin B-cell lymphoma is an aggressive mature B-cell lymphoma that depicts poor treatment response and worse prognosis. The presence of MYC and B-cell lymphoma 2 (BCL2) and/or B-cell lymphoma 6 (BCL6) rearrangements qualifies for triple-hit and double-hit lymphomas (THL/DHL), respectively. We attempted to explore the incidence, distribution, and clinical characteristics of the primary high-grade B-cell lymphoma of the central nervous system (CNS) in our cohort from North India. Methods: All the histologically confirmed cases of primary CNS diffuse large B-cell lymphoma (PCNS-DLBCL) over a period of 8 years were included. Cases showing MYC and BCL2 and/or BCL6 expression on immunohistochemistry (IHC) (double- or triple-expressor) were further analyzed by fluorescence in situ hybridization for MYC, BCL2 and /or BCL6 rearrangements. The results were correlated with other clinical and pathological parameters, and outcome. Results: Of total 117 cases of PCNS-DLBCL, there were seven (5.9%) cases of double/triple-expressor lymphomas (DEL/TEL) (six double- and one triple-expressor) with median age of 51 years (age range: 31–77 years) and slight female predilection. All were located supratentorially and were of non-geminal center B-cell phenotype. Only triple-expressor case (MYC+/BCL2+/BCL6+) demonstrated concurrent rearrangements for MYC and BCL6 genes indicating DHL (n = 1, 0.85%), while none of the double-expressors (n = 6) showed MYC, BCL2, or BCL6 rearrangements. The mean overall survival of the DEL/TEL was 48.2 days. Conclusion: DEL/TEL and DHL are uncommon in CNS; mostly located supratentorially and are associated with poor outcome. MYC, BCL2, and BCL6 IHC can be used as an effective screening strategy for ruling out double/ triple-expressor PCNS-DLBCLs.

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Meriranta, Leo, Annika Pasanen, Marja-Liisa Karjalainen-Lindsberg, Sandeep Dave, and Sirpa Leppa. "Clinical and Biological Features behind Hallmark Aberrations in Diffuse Large B-Cell Lymphoma." Blood 132, Supplement 1 (November 29, 2018): 2976. http://dx.doi.org/10.1182/blood-2018-99-117958.

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Abstract Introduction. Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy with a diverse genomic appearance. To date, the coding genomes of almost 2000 DLBCLs have been recognized, and the translation of this genetic information into clinical practice is awaited. Here, we have investigated translocations and protein expression of the hallmark DLBCL genes BCL2, BCL6 and MYC in a well-characterized sample series. The findings are correlated with gene expression, copy number alterations (CNAs) and exome-wide mutational annotations, and molecular data associated with clinical characteristics and treatment outcome. Methods. A tissue microarray (TMA) was constructed from formalin fixed paraffin embedded (FFPE) tumor tissue of 152 primary DLBCL patients treated with R-CHOP or R-CHOP-like regimen. Translocation status was determined for BCL2, BCL6 and MYC genes with break-apart fluorescent in situ hybridization (FISH). BCL2, BCL6 and MYC protein expression was determined immunohistochemically. RNA sequencing data of the log2 transformed gene expression values and whole-exome sequencing annotations of the mutations and CNAs were derived for each case from the 1001 DLBCLs study (Reddy et. al. Cell 2017; 171:481-494). Results. Overall, 55% of the samples were BCL2+. Of the BCL2+ cases, 58% had an underlying structural variation in the BCL2 locus. In the whole study cohort, structural variants of the BCL2 gene were detected in 35% of the cases, and they were associated with high gene expression and immunoreactivity (Figure 1A). BCL2 translocations were detected in 16% of the cases, and they were mutually exclusive with amplifications. Translocations and co-occurring coding mutations of the BCL2 gene were enriched in the GCB subtype and amplifications in the ABC/non-GCB DLBCLs. In the ABC/non-GCB DLBCLs, BCL2 copy number aberrations were associated with poor survival independent of IPI (Figure 1B). High MYC immunoreactivity (>70% cut-off, 12 % of all cases) was evenly distributed between the subtypes. However, MYC translocations (14% of all cases) were associated with the GCB phenotype and elevated gene expression (Figure 1C). Nonsynonymous mutations of the MYC gene were only seen in the translocated cases. Co-occurring MYC and BCL2/BCL6 translocations (Double hit lymphomas, DHL) were recognized in 5.6% cases, most of which were GCB DLBCLs with poor outcome (Figure 1D). Dual protein expression (DPE) of BCL2 and MYC was detected in 9.5% of the cases. DPE lymphomas were evenly distributed between the subtypes, and they had adverse prognostic significance independent of IPI and molecular subtype (Figure 1D). BCL6 translocations (15% of the cases) did not associate with elevated gene expression or coding mutations of the BCL6 gene (Figure 1E). Translocations were more prevalent in the non-GCB than the GCB DLBCLs and mutually exclusive with the MYD88 L265P mutations. Furthermore, BCL6 translocation status highlighted a subgroup of patients with a favorable outcome in the non-GCB DLBCLs independent of IPI (Figure 1F). Conclusions. Our study characterizes the prevalence and clinical impact of hallmark structural variations in DLBCL. The results dignify structural, mutational and expression analysis of BCL2, BCL6 and MYC in the clinical practice, and increase our understanding of different entities within the well-established molecular subtypes. Figure 1. A, C, E) Interplay between structural variants, gene expression, and nonsynonymous SNVs of BCL2, MYC and BCL6, and with immunohistochemical staining scores for BCL2 and MYC proteins are illustrated. B) CNAs of BCL2 and poor survival in patients with non-GCB DLBCL. D) DHLs and DPEs (other than DHL associated) and poor survival. F) BCL6 translocations and favorable outcome in patients with non-GCB DLBCL. Figure 1. Figure 1. Disclosures Leppa: Roche: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy; Bayer: Research Funding.

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Pajor, László, József Kun, Róbert Herczeg, Bence Gálik, Zsombor Ritter, Anett Baliko, Géza Hegedűs, et al. "A diffúz nagy B-sejtes limfóma fenotipikus, citogenetikai és expressziós profil heterogenitása – Magyarországi multicentrikus tanulmány." Hematológia–Transzfuziológia 55, no. 4 (April 4, 2023): 154–63. http://dx.doi.org/10.1556/2068.2023.00157.

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A diffúz nagy B-sejtes limfóma 5 éves általános túlélése a mai kezelések mellett 60–70%, melynek hátterében a betegség komplex heterogenitása állhat.CélkitűzésMagyarországi multicentrikus tanulmányban a betegség fenotipikus, citogenetikai, genomexpressziós profil- és geográfiai heterogenitásának vizsgálata.MódszerA 276 formol-paraffinos betegmintát Hans' algoritmus és dupla protein expresszor státusz alapján klasszifikáltuk. A IGH::MYC, IGH::BCL2, BCL6 gén átrendeződéseket, valamint a MYC, BCL2 és BCL6 gének nyerését interfázis citogenetikával vizsgáltuk. Az RNA-seq-alapú génexpressziós profilvizsgálat 173 formol-paraffinos mintán volt elvégezhető.EredményekA Hans' fenotípus alapján 103 (37,3%) germinális centrum B-sejt-szerű és 173 (62,7%) nem germinalis B-sejt-szerű limfómát azonosítottunk, mely besorolás 82,6%-os megegyezést mutatott a genomexpressziós profilstratifikációval. Tripla aberrációt mutató limfóma nem fordult elő. Izolált IGH::MYC átrendeződés, valamint MYC, BCL2, BCL6 géntöbblet mindkét Hans' csoportban jelen volt. Az IGH::BCL2 átrendeződés izoláltan vagy kombinációban, szignifikánsan és kizárólag a germinális centrum B-sejt-szerű csoportban volt azonosítható, míg a BCL6 átrendeződés szignifikáns halmozódást mutatott a nem germinális centrum B-sejt-szerű Hans' csoportban. A dupla protein expresszor fenotípus pozitív prediktív értéke mindkét Hans' csoport molekuláris alcsoportjaira alacsony, a 0,04–0,19, illetve a 0,12–0,30, tartományba esett, míg negatív prediktív értéke mindkét főcsoport összes releváns molekuláris alcsoportjában 1,00-nek felelt meg.KövetkeztetésekA IGH::MYC átrendeződés nem Hans' csoport specifikus genotípus. Az IGH::BCL2 átrendeződés germinalis centrum, a BCL6 átrendeződés pedig a nem germinalis centrum B-sejt-szerű limfóma fémjele. A dupla protein expresszor negatív fenotípus mellett IGH::MYC és/vagy IGH::BCL2 átrendeződés nem fordult elő.

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Patel, Priyank P., Alison Zeccola, Vishala T. Neppalli, Juan J. Gu, Cory Mavis, Sheila Sait, and Francisco J. Hernandez-Ilizaliturri. "Pre-Clinical Investigation of Targeted Therapies for Double Hit Diffuse Large B-Cell Lymphoma (DH-DLBCL)." Blood 126, no. 23 (December 3, 2015): 5122. http://dx.doi.org/10.1182/blood.v126.23.5122.5122.

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Abstract Background: Molecular studies divide DLBCL into three subtypes with distinct pathogenesis and clinical outcomes: activated B-cell (ABC), germinal center B-cell (GCB) and primary mediastinal lymphoma (PML). Florescence in situ hybridization (FISH) studies identified another subgroup of DLBCL, classified as DH-DLBCL, with a poor clinical outcome harboring concurrent gene rearrangements of the c-MYC, BCL2 and/or BCL6 proto-oncogenes, resulting in the over-expression of c-Myc, Bcl2 and Bcl6 proteins. DH-DLBCL has inferior response rates (RR) to rituximab-based chemotherapy, and a shorter progression-free survival (PFS)/overall survival (OS). DH-DLBCL is characterized by de-regulation of apoptosis and cell cycle progression, resulting in rapid cellular proliferation and resistance to apoptotic stimuli. In ABC-DLBCL, anti-apoptotic factor MCL-1 is implicated in poor prognosis leading to resistance to standard chemotherapy. C-MYC transcriptionally upregulates Mcl1. Translocation of c-MYC in DH-DLBCL may contribute to the aggressive phenotype and chemotherapy resistance via the MCL-1 pathway. We hypothesize that dual inhibition of both anti-apoptotic proteins BCL2 and MCL1 is an effective strategy in inducing lymphoma cell death in DH-DLBCL. Materials & Methods: At the pre-clinical level, we studied novel therapeutic strategies targeting key-regulatory pathways abnormally enhanced by the dual BCL2/BCL6 and c-MYC gene rearrangements or amplification using DH lymphoma cell lines (Val, DOHH-2, ROS-50). We evaluated the therapeutic value of three novel agents targeting BCL2 (ABT199), c-MYC (JQ-1), and cell cycle regulatory proteins (p21) and other BCL2 family members affecting ABT199 activity (carfilzomib (CFZ), an irreversible proteasome inhibitor) in a panel of DH-DLBCL cell lines. We retrospectively evaluated our single institution outcome experience over the last 15 years in DH-DLBCL patients. Using the lymphoma translational database that includes 611 DLBCL patients, we identified 30 patients (M=17/F=13) with aberrations in c-MYC and BCL2 or BCL6 by FISH. Demographic characteristics and clinical data were collected and analyzed. Results: In vitro, ABT199, JQ-1, and CFZ induced cell death in a dose- and time-dependent manner. Significant synergistic activity was observed by combining ABT199 with CFZ and to a lesser degree with JQ-1. Subsequently, we studied the outcome of DHL patients treated at our institute. Mean age at diagnosis was 63 years, mostly Caucasians (N=28). Using the Han's algorithm, 21 of the DH-DLBCL were GCB, 8 were non-GCB, and 1 unclassifiable. 22 patients had rearrangement of c-MYC and BCL2/ or BCL-6 by FISH and 8 had gain/amplification/aneuploidy at these loci. At diagnosis, 96% (n=29) patients presented with stage III/IV, 67% (n=20) with High-intermediate/High IPI score, and 77% (n=23) had extra nodal disease. Front-line chemo-immunotherapy included 1) standard doxorubicin-containing regimens: R-CHOP (N=11) or R-EPOCH (N=8), or 2) intensified regimens: R-DHAC (N=3) and R+HyperCVAD/R+HDMTXCytarabine (N=8). Prophylaxis IT chemotherapy was administered to 21 (70%) patients. The complete remission (CR) rate was 67% (n=20) and 37% (n=11) patients underwent HDC-ASCS (N=9)/allo-BMT (N=2) in first (N=9) or second-remission (N=2). The use of intensified regimens was associated with a non-statistically significant improvement is PFS and OS. Similarly, an improvement in OS was observed among patients receiving HDC-ASCT/allo-BMT as consolidation. As previously noted, CNS prophylaxis was associated with an improvement in OS. Mcl-1 and other Bcl-2 family members expression levels are been determined by IHC. These results highlight the poor clinical outcome of this patient population and the need for alternative therapeutic options. Conclusion: Our data suggests that ABT199 exhibited strong synergistic activity with CFZ. Dual targeting of BCL2 and c-MYC pathways results in synergistic activity in DHL cell lines. Of interest, this pharmacological interaction could be related to the effects of proteasome inhibition on MCL1 and p21 levels in lymphoma cells, further enhancing the activity of ABT199. Using combination therapy to inhibit c-MYC and the proteasome and in turn decreasing MCL1 will render ABT-199 more effective and be a more potent combination in causing apoptosis and lymphoma cell death. Further pre-clinical work is ongoing. Disclosures No relevant conflicts of interest to declare.

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Saksena, Annapurna, Parth Desai, Zhuang Zuo, Jie Xu, Pei Lin, Adam C. Seegmiller, C. Cameron Yin, et al. "MYC/BCL2 Double Hit Lymphoma: What Really Matters." Blood 126, no. 23 (December 3, 2015): 3909. http://dx.doi.org/10.1182/blood.v126.23.3909.3909.

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Abstract Introduction: MYC/BCL2 double hit lymphoma (DHL), defined as a large B-cell lymphoma with concurrent MYC and BCL2 translocations, is the most common type of DHL. Although multiple studies focused on DHL have been published, several issues regarding impact on prognosis remain controversial including: 1) history of low grade B cell lymphoma; 2) morphology (diffuse large B-cell lymphoma [DLBCL] versus B cell lymphoma unclassifiable with features intermediate between DLBCL and Burkitt lymphoma [BCLU)]; 3) Absence or low expression of MYC or BCL2; 4) MYC translocation partner gene; and especially 5) most effective therapy. The aim of this study was to attempt clarify the prognostic importance of these factors in DHL. Methods: 157 patientsdiagnosed with MYC/BCL2 DHL between 2003 and April 2015 at two institutions were included in this study. MYC and BCL2 gene rearrangement were confirmed by FISH using a MYC breakapart probe and BCL2 and IGH dual color dual fusion probes. BCL6/3q27gene status was tested either by FISH using breakapart probe or by karyotype. MYC partner gene was identified by karyotype. MYC/BCL2 DHL cases were identified if they had rearrangements of MYC and BCL2 but not BCL6. Positive for MYC or BCL2 by immunohistochemistry was defined by >40% and >50% of lymphoma cells showed positive expression, respectively. Patient survival was analyzed using the Kaplan-Meier method and compared using the log-rank test. Fisher's exact test was used to compare the clinicopathologic features. Statistical analysis was performed using SPSS 23 software. Results: There were 103 men and 54 women with a median age of 61 years (range, 18-87). 110 patients had de novo disease and 47 patients had a history of low-grade B-cell NHL, mostly follicular lymphoma. The clinicopathologic features were similar (P>0.05) between patients with a history of low-grade B-cell NHL and patients with de novo NHL, and therefore analysis was performed on all 157 DHL cases. Using the 2008 WHO classification, there were 91 DLBCL, 61 BCLU, and 5 composite lymphoma (4 DLBCL + follicular lymphoma and 1 DLBCL + B-lymphoblastic lymphoma). 99% of cases had a germinal center B-cell immunophenotype by the Hans algorithm. MYC expression was observed in 39/47 (83%) and BCL2 in 129/141(91%) of cases. MYC and BCL2 dual expression was present in 34/46(74%) cases. Of the 39 cases assessed, the MYC translocation partner was IGH in 13, IG light chain in 19, and a non-IG gene in 7 cases. 144 patients had complete treatment information: 61 received the R-CHOP regimen initially, 31 R-EPOCH, 29 R-HCVAD, and 23 various other chemotherapy regimens. 39 patients also received stem cell transplant (SCT) including 31 autologous and 8 allogeneic. 62 patients reached complete remission (CR) after initial chemotherapy. The median overall survival was 19 months. In a univariate analysis that evaluated 17 clinicopathologic parameters including those mentioned in introduction, extranodal sites of disease, bone marrow involvement, CNS involvement, advanced stage, and high/high-intermediate International Prognostic Index score were associated with a worse overall survival (OS, P<0.05), whereas CR and SCT were associated with a better OS (P<0.05). By multivariate analysis, stage, IPI, SCT, and CR predicted OS (Table 1 and Figure 1). Conclusion: MYC/BCL2 DHL are clinically aggressive B cell lymphomas with a germinal center phenotype and patients have a poor prognosis. In this study, a history of low grade B cell lymphoma, morphology (DLBCL vs BCLU), MYC expression, BCL2 expression, MYC/BCL2 dual expression (double expresser lymphoma), MYC translocation partner gene, and initial chemotherapy regimens were not associated with overall survival. The independent prognostic factors shown by multivariate analysis were IPI score, stage, achievement of CR, and a therapeutic regimen including SCT. Table 1. Multivariate analysis Features HR 95% CI P BM involvement 0.92 0.48 - 1.80 0.817 Extranodal sites ≥ 2 1.12 0.48 - 2.65 0.793 Stage III /IV vs I/II 34.45 4.92 - 241.31 <0.001 IPI (H/H-I vs L/L-I) 3.00 1.14 - 7.77 0.026 Initial Chemotherapy R-EPOCH vs R-CHOP 1.17 0.49 - 2.84 0.723 R-HCVAD vs R-CHOP 0.95 0.47 - 1.93 0.894 Stem cell transplant 0.22 0.10 - 0.46 <0.001 CR after initial chemotherapy 0.14 0.07 - 0.30 <0.001 Figure 1. Figure 1. Disclosures Reddy: ImmunoGen: Consultancy; PCYC: Consultancy; Gilead: Other: Speaker; Seattle Genetics: Consultancy; Celgene: Consultancy, Research Funding.

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Khurana, Arushi, Raphael Mwangi, James R. Cerhan, Jonathon B. Cohen, Jennifer R. Chapman-Fredricks, Jonathan W. Friedberg, Christopher R. Flowers, et al. "Comparing Clinical Characteristics and Outcomes of MYC and BCL6 Double Hit Lymphoma (DHL- BCL6) with Other Aggressive B-Cell Lymphomas: Understanding the Impact of New Who and International Consensus Classifications." Blood 142, Supplement 1 (November 28, 2023): 67. http://dx.doi.org/10.1182/blood-2023-190316.

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Background: High Grade B cell Lymphoma (HGBL) with MYC and BCL2 and/or BCL6 rearrangements(R) was introduced as an entity in 2016 by the WHO revised 4 th edition. In 2022, both the WHO 5 th edition (beta version) and the International Consensus Classification (ICC) separated DHL- BCL2 (+/- BCL6-R)from DHL- BCL6 given differences in biology . However, while the ICC has maintainedDHL- BCL6 as a provisional entity, the WHO has removed the category, thus removing the requirement to FISH for BCL6-R in this setting. Clinical data on DHL- BCL6 is much more limited, as these cases represent only 10-20% of DHL and have been combined with BCL2-R cases in prior studies. Outcomes are variable in retrospective studies with no consistent data on prognosis or optimal therapeutic strategies. By retaining the category of DHL-BCL6 as a provisional entity, the ICC emphasized the need for further, multicenter, prospective studies evaluating the clinical and biological features of this disease. We herein report a comprehensive comparison of clinical characteristics and outcomes in patients with DHL- BCL6 compared to diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS); DLBCL with MYC rearrangement only; DHL- BCL2; and HGBL, NOS in a large, multicenter, prospective cohort of patients from Lymphoma Epidemiology of Outcomes (LEO). Methods: Adult patients with newly diagnosed large B-cell or HGBL were enrolled within 6 months of diagnosis at one the 8 LEO cohort academic medical centers in the US between 2015 and 2020. Baseline characteristics were abstracted at the time of diagnosis per protocol. Based on FISH data patients were further sub mgrouped into DLBCL, NOS (without MYC rearrangement); MYC-R DLBCL, NOS; HGBL, NOS; DHL- BCL2 and DHL- BCL6. Event-free survival (EFS) was defined as the time from diagnosis until progression/relapse, retreatment, or death. Overall survival (OS) was defined as the time from diagnosis until death due to any cause. Results: A total of 1526 eligible patients were identified during this time period. All FISH data was available at the time of diagnosis and the choice of treatment was based on physician discretion. Median age at diagnosis was 63 years (IQR 53-72), with 148 (10%) patients in the AYA category, and 128 (8%) patients > 80 years. 58% (891) were male, 11% self identified as Hispanic or Latino, and 7% as Black/African American. The median diagnosis to treatment interval (DTI) was 20 days (IQR 12-32), and 33% had DTI < 14 days. The FISH-based subgroups were MYC-negative DLBCL, NOS (N=1146, 75%), MYC-R DLBCL,NOS 227 (N = 96, 6%), DHL- BCL2 (N=154, 10%), DHL- BCL6 (N=38, 3%), and HGBL, NOS (N=92, 6%). When available, COO by Hans algorithm was 92% GCB in DHL- BCL2 and 50% GCB in DHL- BCL6. Clinical characteristics can be found in the table. At a median follow-up of 49 months (IQR 36-67), 490 patients (32%) had an event and 356 patients (23%) died. EFS at 24 months (EFS24) was 75% (95% CI: 73-77). Patients with DHL- BCL6 were younger at diagnosis (median 60 years), had more extranodal site involvement (40%), more often stage III/IV disease (70%), and more often treated with a higher intensity regimen than R-CHOP (69%) compared to DLBCL,NOS and MYC-R DLBCL. DHL- BCL6 also had fewer patients that were males (47%), with DTI <=14 days (33%), NCCN IPI ≥ 4 (45%), elevated LDH (53%) than HGBL, NOS and DHL- BCL2. The 2-year EFS and OS rates were noted to be significantly better in the DHL- BCL6 (EFS 79%, 95% CI: 67-93; OS 92%, 95% CI: 84-100) as compared to DHL- BCL2 (EFS 58%, 95% CI: 50-66; OS 70%, 95% CI 63 - 78) and HGBL, NOS (EFS 74%, 95% CI: 65-84; OS 74%, 95% CI: 65-84 ), (Figure 1) but were comparable to that of DLBCL, NOS (EFS 78%, 95% CI: 76-81; OS 87%, 95% CI: 86-89). Conclusions: Our data support separating DHL- BCL6 from DHL -BCL2 as these patients form a unique subgroup with some clinical characteristics comparable to both DLBCL, NOS as well as HGBL, NOS and DHL- BCL2 subtypes. In this cohort, clinical outcomes are more comparable to DLBCL, NOS than DHL- BCL2 or HGBCL, NOS. More frequent use of intensive chemotherapy in DHL- BCL6 compared with DLBCL may account for this finding, although larger multicenter studies are needed. Our results support continued identification of DHL- BCL6 in the clinical setting to better understand optimal therapy and biology of this cohort.

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Misyurina, A. E., S. K. Kravchenko, A. M. Kovrigina, A. U. Magomedova, L. V. Plastinina, T. N. Obukhova, A. V. Misyurin, et al. "The role of translocations involving c-MYC/8q24, BCL2/18q21 and/or BCL6/3q27 genes in patients with follicular lymphoma. Retrospective analysis of single - centre data." Terapevticheskii arkhiv 91, no. 7 (July 15, 2019): 52–62. http://dx.doi.org/10.26442/00403660.2019.07.000070.

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Aim of the issue was to compare clinical characteristics and treatment results of patients with follicular lymphoma (FL) with translocations involving loci of c-MYC/8q24, BCL2/18q21 and/or BCL6/3q27 genes and patients with high - grade B-cell lymphoma [High - grade B-cell lymphoma (HGBL), double - hit (DH)]. Materials and methods. Since 2004 to 2017 years in National Research Center for Hematology 12 patients with high - grade B-cell lymphoma double - hit (HGBL DH) and 6 FL patients with translocations involving c-MYC and BCL2 and/or BCL6 had been treated. We performed a comparative analysis of clinical characterisctics in both groups. As primary endpoints was assessed frequency of complete remission (CR) or progressive disease (PD); as secondary endpoints - overall (OS) and event - free survival (EFS). Results. 5 patients with HGBL DH had c-MYC/BCL6, 7 - c-MYC/BCL2 rearrangements; 2 patients with FL had c-MYC/BCL2, 3 - c-MYC/BCL6, 1 - c-MYC/BCL2/BCL6 rearrangements. FL was represented by grade 3A in 2, grade 3B - in 4 cases, 3 of them had large - cell transformation. In HGBL DH and FL patients had no significant differences in clinical characteristics. The majority of patients had a widespread tumour, increased LDH activity, high frequency of extranodal and bone marrow involvement. Ki-67 expression level was lower in patients with FL (p

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Landsburg, Daniel J., Marissa K. Falkiewicz, Jennifer J. D. Morrissette, April M. Schrank-Hacker, Sunita Dwivedy Nasta, Jakub Svoboda, Stephen J. Schuster, et al. "Patients with "Single-Hit" but Not MYC -Amplified Non-Burkitt High-Grade B Cell Non-Hodgkin Lymphomas Experience Poor Survival Outcomes and May Benefit from Intensive Induction Therapy." Blood 126, no. 23 (December 3, 2015): 2696. http://dx.doi.org/10.1182/blood.v126.23.2696.2696.

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Abstract Introduction While patients (pts) with diffuse large B cell lymphoma (DLBCL) and B cell lymphoma unclassifiable with features intermediate between DLBCL and Burkitt lymphoma (BCLU) harboring rearrangement of MYC (MYC-R) face a poor prognosis as compared to DLBCL/BCLU pts without MYC-R, the prognosis of DLBCL/BLCU pts with MYC-R in the absence of rearrangements of BCL2 (BCL2-R) and BCL6 (BCL6-R) has not clearly been reported in the literature. Additionally, it is not well known whether amplification of MYC in the absence of MYC-R portends a poor prognosis for DLBCL/BCLU pts. Here, we analyze outcomes for these pts in comparison to DLBCL/BCLU pts without MYC-R or MYC amplification. Methods Pts diagnosed with DLBCL or BCLU treated at the University of Pennsylvania and Northwestern University from 3/2002-3/2015 whose diagnostic specimens underwent fluorescence in situ hybridization for MYC-R with8q24 breakapart and/or t(8;14)(q24;q32) fusion probes were included in this analysis. Pts with primary CNS and HIV-associated lymphoma were excluded. Cases with MYC-R but not BCL2-R and BCL6- R were defined as single hit (SH), cases with MYC-R as well as BCL2 -Rand/or BCL6-R as double hit (DH), cases with >4 copies of MYC as amplified (MYC amp) and cases without MYC-R and ≤4 copies of MYC as normal (MYC normal). Therapy was given at the discretion of the treating clinician. Progression free survival (PFS) was defined as time from diagnosis to radiographic progression, regimen change, death or last follow-up. Overall survival (OS) was defined as time from diagnosis to death or last follow-up. Data were censored on 7/1/15. Results 224 pts were included in the full analysis: 190 MYC normal, 19 SH and 15 MYC amp. An additional 46 DH pts were analyzed for PFS and OS only. No pts were both SH and MYC amp. Pts baseline characteristics were reported as follows: 52% female, 47% age >60 years (yrs), 66% LDH >normal, 62% stage ≥3, 15% lymphomatous involvement of bone marrow, 11% ECOG performance status (PS) >2, 66% extranodal disease, 29% B symptoms, 42% International Prognostic Index (IPI) score ≥3, 4% BCLU histology and 18% low-grade transformation. Only the presence of BCLU histology differed significantly between SH and MYC normal pts (26% vs. 1%, p=0.001) and between MYC amp and MYC normal pts (13% vs. 1%, p=0.028). PFS and OS are depicted in Figure 1. For all pts, the median length of follow-up was 15.4 months (mos) (range 0.1-156.1 mos), median PFS not yet reached and median OS not yet reached. Rates of PFS and OS at 2 yrs for MYC normal, SH and MYC amp pts were 72%, 52%, 62% and 81%, 65%, 74%, respectively. When compared to MYC normal pts, SH pts experienced significantly shorter rates of PFS (p=0.043) and OS (p=0.038) at 2 yrs; however, rates of PFS and OS at 2 yrs did not differ significantly between MYC amp and MYC normal pts (p=0.29 and p=0.67, respectively). For comparison, rates of PFS and OS at 2 yrs for DH pts were 32% and 37%, and did not differ significantly from those of SH pts (p=0.26 and p=0.18, respectively). For SH patients, rates of PFS and OS at 2 yrs for those receiving induction therapy with R-CHOP vs. intensive induction (II), defined as either R-EPOCH, R-hyperCVAD or R-CODOX-M/IVAC, were 25% vs. 76% (p=0.13) and 75% vs. 73% (p=0.94), respectively. Baseline characteristics significantly associated with progression on univariate analysis (UVA) were LDH > normal (HR 2.50, 95% CI 1.20-5.17, p=0.014), ECOG PS >2 (HR 2.17, 95% CI 1.05-4.70, p=0.036) and B symptoms (HR 2.49, 95% CI 1.48-4.19, p=0.001); however, only B symptoms remained statistically significant on multivariate analysis (MVA) (HR 2.66, 95% CI 1.41-5.01, p=0.003). Baseline characteristics significantly associated with death on UVA were LDH > normal (HR 3.99, 95% CI 1.19-13.4, p=0.025), ECOG PS >2 (HR 3.19, 95% CI 1.29-7.90, p=0.012), B symptoms (HR 2.70, 95% CI 1.31-5.57, p=0.007) and SH vs. MYC normal (HR 2.59, 95% CI 1.06-6.31, p=0.037); however, no factor remained statistically significant on MVA. Conclusions This analysis of the largest reported series of SH and MYC amp pts suggests inferior rates of PFS and OS at 2 yrs for SH pts, but not MYC amp pts, as compared to MYC normal pts. SH pts receiving II experienced similar rates of PFS and OS at 2 yrs as compared to MYC normal pts. Much like DH pts, SH pts should be considered a poor prognosis subgroup of non-Burkitt high-grade B cell non-Hodgkin lymphomas and identified as candidates for risk-adapted and/or targeted therapies. Figure 1. Figure 1. Disclosures Dwivedy Nasta: Millenium Takeda: Research Funding; BMS: Research Funding. Svoboda:Immunomedics: Research Funding; Celldex: Research Funding; Celgene: Research Funding; Seattle Genetics: Research Funding. Schuster:Genentech: Consultancy; Pharmacyclics: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Hoffman-LaRoche: Research Funding; Janssen: Research Funding; Gilead: Research Funding; Novartis: Research Funding; Nordic Nanovector: Membership on an entity's Board of Directors or advisory committees. Mato:Gilead: Consultancy, Research Funding; Celgene Corporation: Consultancy, Research Funding; Genentech: Consultancy; Pharmacyclics: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pronai Pharmaceuticals: Research Funding; TG Therapeutics: Research Funding. Petrich:Seattle Genetics: Consultancy, Honoraria, Research Funding.

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Adam, Ammar, Kate Byth, Paul Secrist, Alwin Schuller, Corinne Reimer, Deborah Lawson, Terry MacIntyre, and Francoise Powell. "A Dual Bcl-2/xL Inhibitor Induces Tumor Cell Apoptosis in a Hematopoietic Xenograft Model." Blood 124, no. 21 (December 6, 2014): 5304. http://dx.doi.org/10.1182/blood.v124.21.5304.5304.

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Abstract Over-expression of the antiapoptotic proteins Bcl-2 and Bcl-xL provides a common mechanism through which cancer cells gain a survival advantage and become resistant to conventional standard of care therapies. Because Bcl-2 family members play key, but partially overlapping, roles as regulators of apoptosis, simultaneous inhibition of both Bcl-2 and Bcl-xL could serve as a promising anticancer strategy. Clinical validation of this concept has been demonstrated with multiple agents targeting different Bcl2 family members. For example, recent Phase I/II trials of the dual Bcl-2 / Bcl-xL inhibitor Navitoclax demonstrated a 20% response rate in relapsed, refractory CLL patients. However, in this study dosing was often limited by chronic thrombocytopenia, a well established side effect of inhibiting Bcl-xL. Here we disclose for the first time a novel and potent BH3 mimetic (Bcl2-32), with nanomolar binding affinity for Bcl-2 and Bcl-xL, (Ki = 3.3 and 8.5nM respectively). In contrast to Navitoclax which requires daily oral administration for activity, Bcl2-32 has shown promising efficacy on an intermittent dosing schedule that allows full platelet recovery between doses. In this poster, we describe the in vitro and in vivo activity profile of Bcl2-32 in a variety of cell types that highlights its potential as a dual inhibitor of Bcl2 and BclXL. In addition to exhibiting potent single agent anti-cancer activity in a sensitive Acute Lymphocytic Leukemia (RS4; 11) model with (TGI >100%, P < 0.001), Bcl2-32 also potentiates the effectiveness of standard chemotherapeutic agents in less sensitive DLBCL xenograft models. Taken together, these data suggest that Bcl2-32 represents an exciting development opportunity as single agent or in combination in a broad range of hematopoietic malignancies. Disclosures Adam: Astrazenenca: Employment. Secrist:AstraZeneca: Employment.

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50

Shen, Yige, Shu Cheng, Pengpeng Xu, Li Wang, and Weili Zhao. "Clinical and Molecular Features of Patients with Double/Triple Hit Large B-Cell Lymphoma." Blood 142, Supplement 1 (November 28, 2023): 4488. http://dx.doi.org/10.1182/blood-2023-188042.

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Background: High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (HGBL-DH/TH) is a recently defined category in the latest revision of the World Health Organization (WHO) classification, which comprises approximately 5-15% of newly diagnosed DLBCL. This subtype of lymphoma poses numerous challenges from diagnosis to treatment of patients. On the one hand, diagnosis of HGBL-DH/TH requires the accomplishment of fluorescent in-situ hybridization (FISH) to identify the translocations of MYC(8q24) and BCL2(18q21) or/and BCL6(3q27), with no consensus being reached regarding the most applicable population for FISH tests due to high cost and low prevalence. On the other hand, HGBL-DH/TH displays aggressive features, including a high incidence of advanced disease at diagnosis, and inferior efficacy to standard-induced chemical immunotherapy with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Despite several treatment strategies including intensified protocols and hematopoietic cell transplantation (HCT) have been explored, there is no standard regimen to improve outcomes for HGBL patients, and participation in clinical trials is encouraged. Aims: This study aims to investigate the clinical characteristics and prognostic outcomes of HGBL-DH/TH patients, and performed genomic and transcriptomic analyses to link the oncogenic mutations and tumor microenvironment alterations to different DLBCL subgroups. Method:In this study, 107 patients with newly diagnosed HGBL-DH/TH were analyzed. Histological diagnoses were established according to the WHO classification. These HGBL-DH/THs were termed DHL-BCL2 (MYC and BCL2 translocation), DHL-BCL6 (MYC and BCL6 translocation), and THL in our study. DNA sequencing was carried out on 95 patients, for detection of genetic aberrations. Results: Patients with DHL-BCL2 (n=44) and THL (n=15) have similar clinical features, including elevated serum lactate dehydrogenase (LDH), increased proportion of double expression (DE) as well as increased prevalence of non-GCB subtype compared to those with DHL-BCL6 (n=48). With the median follow-up time of 19.3 months (2.5-114.2 months), patients in the DHL-BCL2 and THL group had dismal survival (2-year PFS: 49.3% and 34.2%; 2-year OS: 64.0% and 55.6%) when compared with those in the DHL-BCL6 group (2-year PFS: 63.5%; 2-year OS: 89.3%) (Figure A). Moreover, intensive chemoimmunotherapy or combination with novel targeted agents seemed to improve outcomes in patients with DHL/THL compared with those who received a standard R-CHOP regime. The use of autologous stem cell transplant (ASCT) did not yield a significant improvement in survival for patients who achieved remission after receiving first-line R-DA-EDOCH therapy. However, it is worth noting that there was a trend towards prolonging progression-free survival (PFS) and overall survival (OS) in patients who achieve complete remission (CR) through RCHOP-based treatment and undergo ASCT (Figure B). Compared to DHL-BCL6, the primary genetic lesions in DHL-BCL2 and THL were alterations associating epigenetic regulators like EZH2 and CREBBP, while the primary genetic lesions in DHL-BCL6 were alterations associating cellular differentiation and transcription factors like BTG2, PTPN6, CD70, and BCL6. Correlatively, the EZB genotype was more frequently observed in patients with DHL-BCL2 and THL, while the BN2 genotype was more frequently observed in patients with DHL-BCL6. Conclusion: DHL-BCL2/THL exhibits similar clinical characteristics, prognostic outcomes, and molecular features that set it apart from DHL-BCL6. This implies the need for testing novel agents or therapeutic strategies to expedite treatment development for patients with DHL-BCL2/THL.

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