Dissertations / Theses on the topic 'Chronic lymphocytic leukemia'
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1
Matthews, Christine. "Molecular genetics of chronic lymphocytic leukemia." Thesis, University of Ulster, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.444515.
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Baliakas, Panagiotis. "Reappraising prognosis in chronic lymphocytic leukemia." Doctoral thesis, Uppsala universitet, Institutionen för immunologi, genetik och patologi, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-280943.
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Chronic lymphocytic leukemia (CLL) exhibits remarkable clinical heterogeneity likely reflecting the underlying biological heterogeneity. The genetic landscape of CLL has been recently enriched with mutations within a number of genes proposed as novel prognostic markers. Mounting evidence also supports the pivotal role of the clonotypic B-cell receptor immunoglobulin (BcR IG) in the natural history of CLL. Interestingly, almost 30% of all CLL patients can be assigned to different patient subsets, each defined by expression of a distinct stereotyped BcR IG. Whether stereotyped subsets exhibit distinct clinical behavior is still an issue of debate. The aim of this thesis was to evaluate the prognostic relevance of recurrent gene mutations and to assess the clinicobiological associations and clinical impact of BcR IG stereotypy in CLL. In a cohort of 3490 patients, NOTCH1, SF3B1 and TP53 mutations were enriched within clinically aggressive cases carrying unmutated IGHV genes (U-CLL), frequently co-occurring with trisomy 12, del(11q) and del(17p), respectively. Of note, SF3B1 mutations increased in parallel with increasing timespan between diagnosis and mutational screening. NOTCH1 mutations, SF3B1 mutations and TP53 abnormalities (TP53abs, deletions and/or mutations) correlated with shorter time-to-first-treatment among early stage cases, while in multivariate analysis, only SF3B1 mutations and TP53abs retained independent significance. In a series of 8593 CLL patients, stereotyped subsets showed marked differences in demographics, clinical presentation, cytogenetic aberrations and gene mutational spectrum. Patients within a specific subset generally followed similar clinical courses, whereas patients in different stereotyped subsets—even when displaying similar IG somatic hypermutation status— experienced significantly different clinical outcome. In particular, subset #2 (IGHV3-21/IGLV3-21), the largest overall, was found to exhibit (i) a remarkably high incidence of SF3B1 mutations (44%), alluding to subset-biased acquisition of genomic aberrations, in the context of particular antigenic stimulation; and, (ii) a dismal clinical outcome, distinct from the remaining IGHV3-21 CLL. Our findings strongly support the adverse clinical impact of SF3B1 mutations in CLL in addition to TP53abs. BcR IG stereotypy also emerges as prognostically relevant, further highlighting that an immunogenetic sub-classification of CLL based on BcR IG configuration could refine patient risk stratification.
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Beckwith, Kyle Addison. "Novel Immunotherapeutic Strategies for Chronic Lymphocytic Leukemia." The Ohio State University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=osu1461203257.
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Hing, Zachary Andrew. "Targeting Nuclear Export in Chronic Lymphocytic Leukemia." The Ohio State University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=osu1523543484958313.
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Sevov, Marie. "RNA-based Prognostic Markers in Chronic Lymphocytic Leukemia." Doctoral thesis, Uppsala universitet, Institutionen för genetik och patologi, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-133250.
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Chronic lymphocytic leukemia (CLL) is a heterogeneous disease where a significant proportion of patients will develop an aggressive disease. Today, the mutational status of the immunoglobulin heavy variable (IGHV) genes is one of the strongest prognostic markers in CLL, where unmutated IGHV genes correlate with poor outcome. In addition, IGHV3-21 gene usage is associated with poor prognosis independent of mutational status. Recently, several genes were shown to be differently expressed between IGHV mutated and unmutated CLL and were suggested as prognostic markers. The aim of this thesis was to examine the applicability of these RNA-based prognostic markers in CLL. In papers I and II, the prognostic significance of LPL and TCL1A mRNA expression in CLL was investigated in 140 and 144 patients, respectively. High expression was found to be associated with inferior clinical outcome for both markers. However, CLL cases with mutated IGHV3-21 genes displayed low levels of LPL expression, indicating that LPL cannot identify this poor-risk patient group. In contrast, high TCL1A expression was detected in all IGHV3-21 cases. To elucidate the functionality of LPL in CLL, LPL lipase activity was measured in 33 cases. The lipase activity was found to be invariably low, implying an alternative function for LPL in CLL. In paper III, a comprehensive analysis of five RNA-based markers (LPL, TCL1A, ZAP70, CLLU1 and MCL1) was performed in 252 CLL patients. All RNA-based markers except MCL1 predicted clinical outcome, with LPL being the strongest. Moreover, LPL expression independently predicted overall survival when adjusted for established markers. All of the RNA-based markers added additional prognostic information to established markers, e.g. high LPL expression predicted an inferior outcome in patients with mutated IGHV genes or good-risk cytogenetics. For clinical application, over time stability of prognostic markers is crucial. In paper IV, the expression of LPL, TCL1A, ZAP70 and MCL1 was investigated in samples taken at diagnosis and at a follow-up of seven years in 104 CLL patients. LPL was found to be the most stable marker, displaying high correlation between the sequential samples, whereas ZAP70 and MCL1 varied significantly. TCL1A expression increased at follow-up, which may indicate disease progression as TCL1A promotes cell survival. In summary, this thesis highlights the applicability of RNA-based markers in CLL prognostication, both as single markers or in combination with established markers. In particular, LPL was shown to be the strongest RNA-based marker in terms of prognostic strength and stability.
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Ljungström, Viktor. "Exploring next-generation sequencing in chronic lymphocytic leukemia." Doctoral thesis, Uppsala universitet, Experimentell och klinisk onkologi, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-302026.
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Next-generation sequencing (NGS) techniques have led to major breakthroughs in the characterization of the chronic lymphocytic leukemia (CLL) genome with discovery of recurrent mutations of potential prognostic and/or predictive relevance. However, before NGS can be introduced into clinical practice, the precision of the techniques needs to be studied in better detail. Furthermore, much remains unknown about the genetic mechanisms leading to aggressive disease and resistance to treatment. Hence, in Paper I, the technical performance of a targeted deep sequencing panel including 9 genes was evaluated in 188 CLL patients. We were able to validate 143/155 (92%) selected mutations through Sanger sequencing and 77/82 mutations were concordant in a second targeted sequencing run, indicating that the technique can be introduced in clinical practice. In Paper II we screened 18 NF-κB pathway genes in 315 CLL patients through targeted deep sequencing which revealed a recurrent 4 base-pair deletion in the NFKBIE gene. Screening of NFKBIE in 377 additional cases identified the mutation in ~6% of all CLL patients. We demonstrate that the lesion lead to aberrant NF-κB signaling through impaired interaction with p65 and is associated with unfavorable clinical outcome. In Paper III we sought to delineate the genetic lesions that leads to relapse after fludarabine, cyclophosphamide, and rituximab treatment. Through whole-exome sequencing of pre-treatment and relapse samples from 41 cases we found evidence of frequent selection of subclones harboring driver mutations and subsequent clonal evolution following treatment. We also detected mutations in the ribosomal protein RPS15 in 8 cases (19.5%) and characterization of the mutations through functional assays point to impaired p53 regulation in cells with mutated RPS15. Paper IV aimed at characterizing 70 patients assigned to three major subsets (#1, #2, and #4) through whole-genome sequencing. Besides recurrent exonic driver mutations, we report non-coding regions significantly enriched for mutations in subset #1 and #2 that may facilitate future molecular studies. Collectively, this thesis supports the potential of targeted sequencing for mutational screening of CLL in clinical practice, provides novel insight into the pathobiology of aggressive CLL, and demonstrates the clinical outcome and cellular effects of NFKBIE and RPS15 mutations.
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Cortese, Diego. "Genomic and transcriptomic sequencing in chronic lymphocytic leukemia." Doctoral thesis, Uppsala universitet, Institutionen för immunologi, genetik och patologi, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-303703.
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Identification of recurrent mutations through next-generation sequencing (NGS) has given us a deeper understanding of the molecular mechanisms involved in chronic lymphocytic leukemia (CLL) development and progression and provided novel means for risk assessment in this clinically heterogeneous disease. In paper I, we screened a population-based cohort of CLL patients (n=364) for TP53, NOTCH1, SF3B1, BIRC3 and MYD88 mutations using Sanger sequencing, and confirmed the negative prognostic impact of TP53, SF3B1 or NOTCH1 aberrations, though at lower frequencies compared to previous studies. In paper II, we assessed the feasibility of targeted NGS using a gene panel including 9 CLL-related genes in a large patient cohort (n=188). We could validate 93% (144/155) of mutations with Sanger sequencing; the remaining were at the detection limit of the latter technique, and technical replication showed a high concordance (77/82 mutations, 94%). In paper III, we performed a longitudinal study of CLL patients (n=41) relapsing after fludarabine, cyclophosphamide and rituximab (FCR) therapy using whole-exome sequencing. In addition to known poor-prognostic mutations (NOTCH1, TP53, ATM, SF3B1, BIRC3, and NFKBIE), we detected mutations in a ribosomal gene, RPS15, in almost 20% of cases (8/41). In extended patient series, RPS15-mutant cases had a poor survival similar to patients with NOTCH1, SF3B1, or 11q aberrations. In vitro studies revealed that RPS15mut cases displayed reduced p53 stabilization compared to cases wildtype for RPS15. In paper IV, we performed RNA-sequencing in CLL patients (n=50) assigned to 3 clinically and biologically distinct subsets carrying stereotyped B-cell receptors (i.e. subsets #1, #2 and #4) and revealed unique gene expression profiles for each subset. Analysis of SF3B1-mutated versus wildtype subset #2 patients revealed a large number of splice variants (n=187) in genes involved in chromatin remodeling and ribosome biogenesis. Taken together, this thesis confirms the prognostic impact of recurrent mutations and provides data supporting implementation of targeted NGS in clinical routine practice. Moreover, we provide evidence for the involvement of novel players, such as RPS15, in disease progression and present transcriptome data highlighting the potential of global approaches for the identification of molecular mechanisms contributing to CLL development within prognostically relevant subgroups.
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Dielschneider, Rebecca. "Targeting Susceptible Signaling Pathways in Chronic Lymphocytic Leukemia." Cell Death and Disease, 2014. http://hdl.handle.net/1993/31681.
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Chronic lymphocytic leukemia (CLL) is a cancer of B cells and is the most common leukemia in North America. Current therapies are fraught with challenges, and drug resistance and disease relapse remain common occurrences. Therefore, novel therapies and novel therapeutic strategies are needed to improve CLL therapy. Better yet, therapies targeted at specific weaknesses of CLL cells will ensure maximum efficacy and minimum adverse toxicity. To this end, this thesis focuses on targeting the susceptible BCR pathway and lysosome-mediated cell death pathway using gefitinib and lysosomotropic agents, respectively.
Firstly, the novel use of the tyrosine kinase inhibitor gefitinib was explored. This drug was most effective in aggressive ZAP-70+ CLL cells and cell lines. A similar inhibitor, erlotinib, had no effect in CLL. Gefitinib inhibited phosphorylation of Syk and ZAP-70, prevented downstream kinase activation, and supressed the pro-survival BCR response. ZAP-70 is implicated in the mechanism of action of gefitinib as introduction of ZAP-70 into a B cell line increased their sensitivity to gefitinib.
Secondly, the novel strategy of targeting lysosomes was explored. The lysosomotropic drugs siramesine, nortriptyline, desipramine, mefloquine, and tafenoquine were all found to induce cytotoxicity and lysosome permeabilization. Lysosome permeabilization was accompanied with lipid peroxidation and followed by loss of mitochondrial membrane potential. Compared with healthy B cells, CLL cells were more sensitive to this cell death pathway. This was potentially due to the overexpression of SPP1 and overproduction of sphingosine, which destabilized lysosomes.
Lastly, this thesis explored the clinical utility of these targeted therapies. Both gefitinib and siramesine were more effective in CLL cells than patient T cells. Furthermore, they retained efficacy amid protective stromal cells. Clinical correlations revealed that gefitinib and siramesine were effective in CLL cells with poor prognostic features. Siramesine was more effective in male cells and in previously-treated cells. Gefitinib was most effective in young patients.
Overall, work presented herein demonstrates the efficacy of the tyrosine kinase inhibitor gefitinib and lysosomotropic agents in primary CLL cells. This work investigates the altered biology of the BCR pathway and lysosomes in CLL cells, and takes advantage of these weaknesses using targeted therapies.October 2016
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Chu, Peter P. "Immune-mediated apoptosis of chronic lymphocytic leukemia cells /." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2001. http://wwwlib.umi.com/cr/ucsd/fullcit?p3031939.
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Fogelson, Ben. "Mathematical Model of the Chronic Lymphocytic Leukemia Microenvironment." Scholarship @ Claremont, 2009. https://scholarship.claremont.edu/hmc_theses/219.
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A mathematical model of the interaction between chronic lymphocytic leukemia (CLL) and CD4+ (helper) T cells was developed to study the role of T cells in cancer survival. In particular, a system of four nonlinear advection diffusion reaction partial differential equations were used to simulate spatial effects such as chemical diffusion and chemotaxis on CLL survival and proliferation.
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Lanemo, Myhrinder Anna. "Restricted antigen recognition in B cell chronic lymphocytic leukemia." Licentiate thesis, Linköping University, Linköping University, Faculty of Health Sciences, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-16355.
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Chronic lymphocytic leukemia (CLL) cells are considered to be derived from antigen-exposed B cells. To further explore the antigen-driven selection behind the leukemogenesis of CLL, we performed immunoglobulin (Ig) specificity screening of 7 CLL cell lines and 23 primary CLL clones from patient peripheral blood. We also included a recombinant monovalent monoclonal antibody (mAb) belonging to a subset of CLL cases with identical or semiidentical heavy chain complementarity determining region 3 (HCDR3) of the IGHV3-21 gene rearrangement. We found CLL mAb specificities against vimentin, filamin B, cofilin-1, proline-rich acidic protein 1, cardiolipin, oxidized low density lipoprotein and Streptococcus pneumoniae polysaccarides. These molecules are functionally associated with microbial infection and/or apoptotic cell removal. An antigen-driven selection would therefore imply that CLL B cell precursors are involved in the elimination and scavenging of pathogens and apoptotic cells, which could trigger the development of the disease.
The limited in vitro survival of CLL cells makes Epstein-Barr virus (EBV) immortalization of CLL cells a useful experimental model for studies on antibody-specificity screening. Considering the intricate procedure of EBV transformation of CLL cells and the many false cell lines used worldwide, we also wanted to characterize and evaluate the authentic origin of several previously established CLL cell lines and their normal lymphoblastoid counterparts. Three of the CLL cell lines tested were truly authentic (I83-E95, CLL-HG3 and CII), two had features of a biclonal Ig expression (232B4 and WaC3CD5+), one was only tentatively verified (PGA-1), whereas one cell line could not be verified (EHEB) due to lack of original patient cells for comparison. Two of the presumed normal lymphoblastoid cell lines tested were shown to be a neoplastic CLL clone. This study emphasizes the importance of proper cell line authentication and we will continue to verify additional cell lines not yet proven authentic.
In conclusion, we provide evidence for natural Ab production by CLL cells and suggest that these cells might be derived from B cell precursors involved in the innate immunity and, thus, providing a first-line-defence against pathogens and in elimination of apoptotic cells.
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Grabowski, Pawel. "Telomere length as prognostic parameter in chronic lymphocytic leukemia." Doctoral thesis, Umeå universitet, Patologi, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-39463.
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B-cell chronic lymphocytic leukemia (B-CLL) is the most common leukemia among the adult population in western countries and accounts for 30-40% of all leukemias. With survival time ranging from months to decades, the clinical course of individual CLL patients is highly variable. This heterogeneity and in the end the need for means to identify the patients with less favorable disease has encouraged the search for biomarkers that can predict the prognosis. Telomeres are repetitive structures protecting the chromosomal endings and shorten at each cell division. Telomere length (TL) has been indicated as a prognostic factor both in hematological malignancies and solid tumors. In B-CLL, TL is associated with mutation status of the immunoglobulin heavy chain variable (IGHV) gene and with clinical course. In the present thesis the main aim was to evaluate TL as a biomarker in B-CLL using a quantitative PCR-based method for TL determination. In paper I, TL was shown to be a prognostic factor for stage A and stage B/C patients, whereas IGHV mutation status predicted outcome only in stage A patients. Moreover, IGHV mutated CLL cases were subdivided by TL into two groups with different prognosis, a subdivision not seen for unmutated cases. Interestingly, the IGHV-mutated group with short telomeres had en overall survival close to that of the unmutated cases. Thus, a combination of IGHV mutation status and telomere length gave an improved subclassification of CLL identifying previously unrecognized patient groups with different outcomes. TL correlates with cellular origin of B-cell malignancies in relation to the germinal center (GC). In paper II different B-cell lymphoma/leukemia subtypes were analyzed. Shortest telomeres were found in IGHV unmutated CLLs, differing significantly from IGHV mutated cases. Contrary to this, mantle cell lymphomas (MCL) demonstrated similar TL regardless of IGHV mutation status. TL differed significantly between GC-like and non-GC-like diffuse large B-cell lymphomas (DLBCL) and follicular lymphomas (FL) had shorter telomeres than GC-like DLBCL. Hairy cell leukemias, which display Ig gene intraclonal heterogeneity, had longer telomeres than FLs and non-GC-DLBCL, but shorter than GC-DLBCL. In conclusion, TL seemed not to simply correlate with GC origin. Paper III presents a B-CLL cohort assessed for TL, genomic aberrations, IGHV mutation status, CD38 and ZAP-70 expression. An inverse correlation existed between TL and IGHV homology, CD38 and ZAP-70 expression. The presence of genomic aberrations was similar among patients regardless of TL. In contrast, 13q deletion, a favorable biomarker, was more frequent in patients with long telomeres, while 11q and 17p deletions (markers of less favorable outcome) were more frequent in the subgroup with short telomeres. In paper IV a large group of mainly indolent CLL cases from a population based cohort was studied again showing an association between TL and prognosis, especially in “good” prognosis cases as defined by other biomarkers. Multivariate analysis indicated a strong connection between IGHV mutation status, lipoprotein lipase (LPL) expression and TL. A comparison of TL in diagnostic and follow up samples demonstrated a significant correlation, and also in the follow samples TL constituted a significant biomarker for survival.
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Marr, Helen Judith. "Regulation of CD38 by IRF4 in chronic lymphocytic leukemia." Thesis, University of Newcastle upon Tyne, 2016. http://hdl.handle.net/10443/3244.
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Genome‐wide association analysis identified rs872071, a common variant in the 3’UTR of IRF4, as tagging a risk allele for chronic lymphocytic leukaemia (CLL). The risk allele is significantly associated with expression of CD38, a poor prognostic marker in CLL. IRF4 is a transcription factor with pleiotropic roles in the regulation of B cell development, and interrogation of the CD38 gene identified a number of putative binding sites for IRF4, suggesting that CD38 may be transcriptionally regulated by IRF4. Chromatin immunoprecipitation (ChIP) demonstrated significant IRF4‐CD38 binding at two composite ETS/IRF consensus element (EICE) sites in SU‐DHL‐6 and MEC‐1 mature B cell lines. Furthermore, there was evidence of IRF4‐CD38 binding at these EICE sites in primary CLL lymphocytes in some, but not all, cases. ChIP studies using markers of histone methylation suggested increased transcriptional activation at the IRF4‐CD38 binding sites in MEC‐1 cells with IRF4 knockdown. In contrast, transcriptional activity at these sites appeared to be reduced in SU‐DHL‐6 cells with IRF4 knockdown. Co‐culture of primary CLL lymphocytes on a CD40L‐expressing monolayer led to an upregulation of IRF4 expression, but no consistent effect on CD38 expression. In addition, ChIP studies using markers of histone methylation were suggestive of reduced transcriptional activity at the IRF4‐CD38 binding site after CD40L co‐culture, suggesting that IRF4 may be a negative regulator of CD38 in CLL. Taken together, the evidence indicates that IRF4 binds to the CD38 locus. However, direct experimental evidence for an effect on CD38 expression is lacking. It is necessary to consider that the interaction between IRF4 and CD38 is unlikely to be a linear signal transduction pathway. Indeed the prevailing evidence regarding the function of IRF4 in B cells suggests a complex signalling network involving numerous other transcription factors and cytokines. Furthermore, IRF4 has been suggested as a putative therapeutic target in haematological malignancies including myeloma. Transient IRF4 knockdown using RNA ii interference (RNAi) techniques was tolerated by SU‐DHL‐6, MEC‐1 and lymphoblastoid TK6 cell lines, though cell proliferation in TK6 and SU‐DHL‐6 was significantly impaired. Long‐term stable knockdown was also tolerated in TK6 cells, but not in MEC‐1 cells, suggesting an essential role for IRF4 in maintenance of MEC‐1 cells. Targeted knockdown of IRF4 also sensitised TK6 B cells and MEC‐1 CLL cells to the growth inhibitory effects of fludarabine, a nucleoside analogue used in the treatment of CLL. These findings indicate that IRF4 is necessary to the maintenance of MEC‐1 cells, which represent a CLL cell line model. A greater understanding of the role of IRF4 in the development and maintenance of CLL may indicate new therapeutic targets in CLL. Indeed, a recently developed novel mouse model of CLL has indicated that deficient IRF4 expression predisposes to the development of CLL. However, the role of IRF4 in the maintenance of CLL cells is yet to be determined. The heterogeneous nature of IRF4 expression in primary CLL lymphocytes determined here, and its potentially pleiotropic role in the transcriptional regulation of CD38 in B cells at different stages of differentiation, suggest that if IRF4 is a key player in the maintenance of the leukaemic clone, its role may be context or patient specific, and dependent on other signalling components or somatic genetic abnormalities.
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Browning, Rebekah L. "Combination Therapies with Interleukin-21 in Chronic Lymphocytic Leukemia." The Ohio State University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=osu1429719855.
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Chang, Hsu-Hsiang. "The tumor microenvironment of B-cell chronic lymphocytic leukemia." Diss., View abstract only; access to full text of dissertation for UC campuses will be available after September 1, 2010, 2008. http://wwwlib.umi.com/cr/ucsd/fullcit?p1457295.
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Thesis (M.S.)--University of California, San Diego, 2008.Title from first page of PDF file (viewed November 10, 2008). Available via ProQuest Digital Dissertations. Includes bibliographical references (p. 52-56).
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Birerdinc, Aybike. "Role of KCNRG in B-CELL chronic lymphocytic leukemia." Fairfax, VA : George Mason University, 2008. http://hdl.handle.net/1920/3365.
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Thesis (Ph.D.)--George Mason University, 2008.Vita: p. 175. Thesis director: Ancha Baranova. Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biosciences. Title from PDF t.p. (viewed Jan. 8, 2009). Includes bibliographical references (p. 156-174). Also issued in print.
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Wang, Qiao. "Analysis of the role of invariant V[alpha]24+NKT cells in the pathogenesis of chronic lymphocytic leukaemia /." [St. Lucia, Qld.], 2001. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe16185.pdf.
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Norberg, Maria. "In Vitro Drug Sensitivity and Apoptosis in Chronic Lymphocytic Leukemia." Doctoral thesis, Uppsala universitet, Institutionen för genetik och patologi, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-120299.
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Chronic lymphocytic leukemia (CLL) is a heterogeneous malignancy displaying varying clinical outcome, where molecular markers today can divide patients into prognostic subgroups. Despite the introduction of new agents for treatment, remissions are usually not sustained in CLL and resistance towards treatment can partly be explained by aberrant apoptosis. The aim of this thesis was to find new drugs for CLL patients resistant to conventional therapy and to analyze genes involved in apoptosis within different prognostic subgroups. In paper I-II, the in vitro activity of substances was investigated using the fluorometric microculture cytotoxicity assay (FMCA). When evaluating rapamycin (paper I), an inhibitor of mTOR, in 97 tumor samples from different entities, CLL was found to be one of the most sensitive tumor types. Combination experiments on patient CLL cells indicated that rapamycin acted synergistically with the CLL drugs vincristine and chlorambucil. An investigation of 20 anti-cancer agents in cells from 40 CLL patients (paper II) revealed that prednisolone and rolipram displayed high activity in poor-prognostic patients, in particular IGHV unmutated CLL. Furthermore, when used in combination these agents were found to produce a synergistic effect. In paper III, the anti-apoptotic BCL2 family member BFL1 was evaluated in 37 CLL cases. Levels of BFL1 were higher in fludarabine-resistant patients compared to fludarabine-sensitive patients. In addition, the high expression of BFL1 inversely correlated to fludarabine-induced apoptosis in CLL cells. A single nucleotide polymorphism in the anti-apoptotic BCL2 gene (-938C>A) has been suggested as a novel poor-prognostic marker in CLL. In paper IV, we investigated this BCL2 polymorphism in 268 CLL patients and correlated genotypes to clinical data. However, no association could be confirmed between this polymorphism and clinical outcome or established prognostic markers. In conclusion, this thesis has shown that rapamycin is a potential drug for treatment in CLL. Furthermore, prednisolone and rolipram were identified as interesting candidates for treatment of poor-prognostic patients. Finally, the anti-apoptotic protein BFL1 may contribute to chemoresistance and hence represents a potential therapeutic target in CLL, whereas from our data, the BCL2 -938C>A polymorphism does not appear to have any prognostic significance.
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Bin, Kaderi Mohamed Arifin. "Assessment of Novel Molecular Prognostic Markers in Chronic Lymphocytic Leukemia." Doctoral thesis, Uppsala universitet, Hematologi och immunologi, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-110371.
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The clinical course of chronic lymphocytic leukemia (CLL) is highly heterogeneous, which has prompted the search for biomarkers that can predict prognosis in this disease. The IGHV gene mutation status and certain genomic aberrations have been identified as reliable prognostic markers of clinical outcome for this disorder. However, the search for more feasible prognostic markers in CLL is still being pursued. Recently, certain single nucleotide polymorphisms (SNPs) in the GNAS1, BCL2 and MDM2 genes and the RNA expression levels of the LPL, ZAP70, TCL1, CLLU1 and MCL1 genes were suggested as novel prognostic markers in CLL. In papers I-III, we performed genotyping analyses of the GNAS1 T393C, BCL2 -938C>A and MDM2 SNP309 polymorphisms in 268-418 CLL patients and related the genotypes with clinical data. Association studies between the polymorphisms and established prognostic markers (i.e. IGHV mutation status, genomic aberrations, CD38 expression) were also performed. Our studies did not find any significant relationship between these SNPs with either clinical outcome or other known prognostic markers in CLL. In paper IV, we measured the RNA expression levels of LPL, ZAP70, TCL1, CLLU1 and MCL1 in 252 CLL cases and correlated these levels with clinical outcome. Here, we verified that high expression of all these RNA-based markers, except MCL1, were associated with an unfavourable prognosis. We also confirmed a close relationship between IGHV mutation status and the RNA-based markers, especially for LPL and CLLU1 expression. Among the RNA-based markers, multivariate analysis revealed LPL expression as the strongest independent prognostic marker for overall survival and time to treatment. Furthermore, the RNA-based markers could add further prognostic information to established markers in subgroups of patients, with LPL expression status giving the most significant results. In summary, data from papers I-III could not verify the GNAS1 T393C, BCL2 -938C>A and MDM2 SNP309 polymorphisms as prognostic markers in CLL. Future SNP markers must hence be confirmed in large, independent cohorts before being proposed as prognostic marker in CLL. In paper IV, we conclude that LPL expression appears to be the strongest among the RNA-based markers for CLL prognostication. Further efforts to standardize LPL quantification are required before it can be applied in the clinical laboratory to predict clinical outcome in this disease.
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Olsson, Anna. "Molecular characterization of apoptosis in B-cell chronic lymphocytic leukemia /." Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-267-5/.
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Wijaya, Ferry. "Prognostic factors for survival in patiens with chronic lymphocytic leukemia." Diss., lmu, 2012. http://nbn-resolving.de/urn:nbn:de:bvb:19-151501.
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Bramson, Jonathan. "Nitrogen mustard drug resistance in B-cell chronic lymphocytic leukemia." Thesis, McGill University, 1994. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=28690.
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Previous studies of nitrogen mustard drug resistance in B-cell chronic lymphocytic leukemia (B-CLL) indicated that resistance was a result of enhanced DNA repair associated with increased expression of two DNA repair genes, ERCC-1 and alkyl-N-purine DNA glycosylase. The aim of this thesis was to expand upon these observations and solidify the link between DNA repair and nitrogen mustard drug resistance. Contrary to our expectations, overexpression of ERCC-1 in CHO cells produced increased sensitivity to melphalan and cisplatin. No correlation was found between ERCC-1 expression and nitrogen mustard resistance in B-CLL, when analyzed in a larger cohort by both Northern and western blots, nor was there evidence of altered expression of a second nucleotide excision repair gene (NER), ERCC-2. Overexpression of alkyl-N-purine DNA glycosylase in CHO cells failed to produce melphalan resistance. Nitrogen mustard resistant B-CLL lymphocytes displayed cross-resistance to the bifunctional agents, mitomycin C and cisplatin, but not to UV or methyl methanesulfonate, supporting a role for enhanced crosslink repair in the resistant phenotype. Poly(ADP-ribose) polymerase (PARP) has been identified as a binding protein which can recognize melphalan damaged DNA. This binding appears to result from nicks induced by the melphalan treatment and can be inhibited if the DNA is alkylated with melphalan in the presence of methoxyamine. PARP expression was the same in both sensitive and resistant lymphocytes. When 3-aminobenzamide was used to inhibit PARP, synergy with melphalan was found in 4 of 7 samples we studied. When the DNA synthesis inhibitors, aphidicolin and ara-C, were used to modulate chlorambucil toxicity, synergy was found in both sensitive and resistant populations. There was also evidence for cross-resistance between chlorambucil and ara-C.Thus, our studies indicate that nitrogen mustard resistance in B-CLL correlates with enhanced activity of a crosslink specific repair process. The observation that nitrogen mustard resistance in B-CLL is associated with cross-resistance to mitomycin C, cisplatin and ara-C, through a mechanism other than P-glycoprotein or glutathione, suggests that this model may represent a novel multi-drug resistant phenotype.
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Dubovsky, Jason A. "Epigenetic Modifiers to Augment the Immunogenicity of Chronic Lymphocytic Leukemia." Scholar Commons, 2013. http://scholarcommons.usf.edu/etd/4623.
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Cancer cells employ a litany of immunosuppressive and immunevasive strategies to avoid detection and elimination by the various arms of the innate and adaptive immune system. Many hematologic and solid tumors progressively develop a specialized microenvironment which promotes tissue restructuring inflammation while masking the immune signature of the tumor cells themselves. Chronic lymphocytic leukemia, a malignancy of mature B lymphocytes must constantly balance on the precipice of immune recognition. A mature antigen presenting cell themselves, CLL clonal growth is dependent on the very interactions which, if effective, could potentially lead to their demise. To circumvent this, CLL clones set up unique signatures which promote immune recognition yet provide diversionary signals to the remaining immune armament resulting in profound immune dysfunction.
While the aforementioned immune dysfunction is widespread, the B cell and T cell repertoire are severely impaired during leukemic progression. The lack of healthy B cells due to displacement by malignant B cells results in the obvious loss of an important antigen presenting cell as well as antibody-based immunity. Additionally, deficient interactions with T cells result in anergy and the preponderance of improperly polarized T lymphocytes which are impotent to eliminate both pathogens and leukemic cells. The result of such severe immune dysfunction is chronic infection and progressive disease which is the primary cause of death in CLL patients.
Our research was focused on the premise that alleviating immune dysfunction and providing immunotherapeutic tools will significantly benefit CLL therapy. To this end we developed methods to improve the cellular interaction between CLL cells and T cells a critical step towards improving the antigen presentation capacity of the diseased B cell repertoire. We also identified a therapeutic strategy which can revert the anergic or improperly polarized state of T cells already in circulation allowing those cells to more effectively perform the effector functions necessary to fight pathogenic attack and malignant transformation. Finally, we identified a number of novel targets in CLL which could be used in a vaccinate-induce method to license the elimination of CLL cells by the patient's adaptive immune system. To achieve our goals we utilized a relatively new class of drugs called epigenetic modifiers which specifically alter the chromatin structure resulting in novel genetic signatures which are heritable over cellular generations. The unique properties of these drugs allow for the elicitation of suppressed genetic programs which, when properly controlled, have the potential to reassert healthy lymphocyte functions.
Our studies provide a comprehensive therapeutic initiative which, by simultaneously alleviating the major causes of immune dysfunction in addition to facilitating the use of novel active immunotherapeutic strategies could potentially impact clinical therapy for CLL.
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Reed, Reiss. "Investigating the role of T-cells in chronic lymphocytic leukemia." Thesis, Cardiff University, 2015. http://orca.cf.ac.uk/73613/.
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T-cells appear to have multiple conflicting roles in CLL. On the one hand tumour-specific T-cells could be used to deliver effective immunotherapy; on the other hand, certain T-cell populations may enhance CLL survival and disease progression. The aim of this thesis was to address these contradictory aspects and to provide a deeper understanding of the role of T-cells in CLL. Firstly, candidate peptides from the pro-apoptotic protein Bax were used to activate potential CLL specific T-cells from HLA-A2+ patients. A CD8+ T-cell clone (6C5) was isolated and it’s specificity was initially mapped to (Bax161-170; LLSYFGTPT) and(Bax160–170; GLLSYFGTPT). However, 6C5 failed to recognise HLA-A2+ CLL cells in vitro, and failed to recognise highly purified forms of the peptides. Further characterisation, involving mass spectrometry and HPLC, mapped T-cell specificity to a modified peptide (LLSY(3-tBu)FGTPT). A second strand of this project involved detailed phenotypic analysis of T-cells from CLL patients (n=97) in order to investigate the basis for immune dysfunction. This analysis indicated that patients with an inverted CD4:CD8 ratio (CLLIR), displayed a skewing towards a highly differentiated T-cell phenotype, as well as expression of markers associated with replicative senescence (CD57+, CD27-) within CD4+ and CD8+ T-cell compartments. In addition, CD4+ T-cells expressing markers associated with immunosuppression (PD-1+, TIM-3+) were also increased in CLLIR. Importantly, the inversion of the CD4:CD8 ratio was associated with shorter progression-free survival. Furthermore, the frequencies of distinct T-cell populations were also shown to haveprognostic impact in both univariate analysis (CD4+PD-1+, CD4+CD57+, CD8+CD57+ and CD8+CD27-) and multivariate analysis (CD4+CD27-PD-1+LAG-3+ and CD8+CD27- CD57+PD-1+). To further evaluate the differences between CLLIR and CLLNR patients, preliminary transcriptional analysis was performed, focusing on genes associated with T-cell function. By contrast, transcriptional analysis suggested that genes associated with activation rather than suppression were enriched in CLLIR.
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Shen, Yandong. "The Chronic Lymphocytic Leukemia (CLL) Microenvironment and Novel Targeted Therapies." Thesis, The University of Sydney, 2019. http://hdl.handle.net/2123/20805.
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Activation of the B-cell receptor (BCR), and subsequent signalling via the Bruton's tyrosine kinase (BTK), phosphoinositide-3 kinase (PI3K) and mitogen-activated protein kinase (MAPK), plays a significant role in the pathogenesis of CLL. This thesis aimed to better understand the role of the CLL microenvironment and to investigate novel treatment strategies for targeting CLL cells in the lymph nodes or bone marrow. We demonstrated using the DotScan cluster of differentiation (CD) antibody microarray, that immunophenotypic changes induced on CLL cells by co-culture with fibroblasts expressing the CD40 ligand can be blocked by ibrutinib or idelalisib. These data provide insight on the mechanisms underlying the lymphocytosis observed in patients treated with these agents. We demonstrated that as a single agent the MEK1/2 inhibitor, binimetinib was effective against CLL cells under certain in vitro conditions and that the drug was effective and synergistic with the AKT inhibitor, MK2206, but not idelalisib. These data suggest that this combination of drugs may represent a novel therapeutic option for CLL effective against CLL cells in the tumour microenvironment. Next, we demonstrated efficacy of the dual PI3K/PIM inhibitor, IBL-202 and showed high synergy with the Bcl-2 inhibitor, venetoclax against CLL cells under conditions that mimic the tumour microenvironment and against a TP53 knock-out cell line we derived from the OSU-CLL cell line using the CRISPR-Cas9 system. This combination was synergistic in terms of apoptosis and inhibition of both the proliferative and migratory capacities of CLL cells. These data suggest that IBL-202 in combination with venetoclax may be an effective treatment option for high risk CLL disease. Collectively, the data presented highlight several pathways and novel drugs that may contribute to the development of therapeutic strategies for CLL patients.
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Weiss, David M. "Cancer-Specific Stress and Absolute Lymphocyte Count Trajectories in Patients with Chronic Lymphocytic Leukemia." The Ohio State University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=osu147765209495775.
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Kiaii, Shahryar. "T cells in patients with B-cell chronic lymphocytic leukemia (B-CLL) and multiple myeloma (MM) : an immunological study /." Stockholm : Karolinska institutet, 2007. http://diss.kib.ki.se/2007/978-91-7357-050-3/.
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Chiu, Kam-hung, and 趙錦鴻. "Genetic aberrations in chronic lymphocytic leukaemia as prognostic markers." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2008. http://hub.hku.hk/bib/B41290781.
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Chiu, Kam-hung. "Genetic aberrations in chronic lymphocytic leukaemia as prognostic markers." Click to view the E-thesis via HKUTO, 2008. http://sunzi.lib.hku.hk/hkuto/record/B41290781.
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Juffs, Helen Gwendolyn. "Immunogenicity of B-cell chronic lymphocytic leukemia and prospects for immunotherapy /." [St. Lucia, Qld.], 2001. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe16312.pdf.
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Gomes, Monteiro Lopes Baptista Maria João. "Molecular mechanisms of apoptosis induced by dexamethasone in chronic lymphocytic leukemia." Doctoral thesis, Universitat de Barcelona, 2012. http://hdl.handle.net/10803/92558.
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Glucocorticoids are frequently included in the chemotherapy regimens administered to patients with CLL because they are potent immunosuppressant agents and because they are able to induce apoptosis in CLL cells. Although used from a long time, the molecular mechanisms by which glucocorticoids induce cell death in CLL cells are largely unknown. Interestingly, CLL cells from prognostic groups defined by the mutational load of the IGHV genes and the expression of ZAP70 seem to have different responses to glucocorticoids.
The hypothesis in this thesis is that there are genes or proteins that determine the different response to glucocorticoids among the specific prognostic groups of patients with CLL.
Sensitivity to dexamethasone was analyzed ex vivo in 50 CLL and compared according to IGHV mutational status and/or ZAP70 expression. The response was further compared by gene expression profiling (GEP) of selected cases. Expression of genes of interest was validated by quantitative reverse transcriptase PCR.
Response to dexamethasone is higher in cases with unmutated IGHV/high ZAP70 expression and the levels of induction of the pro-apoptotic BIM gen correlate with the degree of cell death. The different levels of apoptosis induced by dexamethasone observed in the CLL groups defined by ZAP70 expression translate into different profiles of gene expression. These differences are mainly quantitative; cases with high ZAP70 expression show higher levels of gene induction/repression than cases with low ZAP70 expression. Specific analysis of genes of interest performed in a large series disclosed that baseline mRNA and protein expression levels of FKBP5, the co-chaperone of the glucocorticoid receptor, correlate with the extent of CLL cells apoptosis induced by the treatment with dexamethasone. Baseline FKBP5 levels are higher in samples from patients with high ZAP70 expression. GILZ is differentially induced by dexamethasone in ZAP70 expression groups of CLL, being higher in cases with high ZAP70 expression. Induction of GILZ correlates with induction of BIM and levels of apoptosis.
Unmutated IGHV/high ZAP70 CLL cells exhibit better response to dexamethasone treatment, which is accompanied by a differential expression of genes involved in the glucocorticoid-receptor pathway and by an increased induction of genes related to apoptosis.Los glucocorticoides son frecuentemente incluidos en la quimioterapia administrada a pacientes con leucemia linfática crónica (LLC), pues son potentes inmunosupresores e inducen la apoptosis de las células de LLC. Los mecanismos moleculares por los cuales los glucocorticoides inducen la apoptosis de las células de LLC son en gran parte desconocidos. Las células LLC de grupos pronósticos definidos por el estado mutacional de los genes IGHV y por la expresión de ZAP70 parecen tener diferentes respuestas a los glucocorticoides. La hipótesis de esta tesis es que hay genes o proteínas expresados de forma diferente en los grupos pronósticos de pacientes con LLC que determinan los diferentes niveles de apoptosis inducidos por los glucocorticoides. La sensibilidad al glucocorticoide dexametasona, se determino ex vivo en 50 muestras de pacientes con LLC y se comparo en función del estado mutacional de los genes IGHV y/o de la expresión de ZAP70. También se compararan los perfiles de expresión génica (GEP) de casos seleccionados. Los niveles de expresión de los genes de interés se validaran por QRT-PCR. La respuesta a la dexametasona es superior en los casos de LLC con genes IGHV no mutados/alta expresión de ZAP70. Los niveles de inducción del gen proapoptótico BIM se correlacionan con el grado de muerte celular. Los diferentes niveles de apoptosis inducida por dexametasona en los grupos de LLC definidos por la expresión de ZAP70 se traducen diferentes GEP. Las diferencias entre los GEP de cada grupo fueran principalmente cuantitativas, los casos con alta expresión de ZAP70 muestran niveles más altos de inducción/represión génica que los casos con baja expresión. Se observo que los niveles basales de ARNm y proteína de FKBP5, una cochaperona del receptor de los glucocorticoides, se correlacionan con el grado de apoptosis inducida por la dexametasona y que los niveles de FKBP5 son más elevados en los casos con alta expresión de ZAP70. GILZ induce diferencialmente por la dexametasona, observándose mayores inducciones en los casos con alta expresión de ZAP70. La inducción de GILZ se correlaciona con la inducción de BIM y con la magnitud de la apoptosis.
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Imam, Hasan. "Effects of protein kinase inhibitors on chronic lymphocytic leukemia (CLL) cells." Thesis, Linköpings universitet, Institutionen för klinisk och experimentell medicin, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-73883.
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B cell Chronic lymphocytic leukemia (B-CLL) is a neoplastic disorder characterized by accumulation of B lymphocytes due to uncontrolled growth and resistance to apoptosis. Src family kinases (SFKs) are non receptor tyrosine kinases present in the cytosol, which couple with downstream B cell receptor signaling and thus mediate growth, survival, proliferation and antiapoptosis. In CLL cells SFKs are remarkably overexpressed, especially Lyn kinase. This gives the rational to use SFKs inhibitor to treat CLL. Addition of the specific pharmacological inhibitors of SFKs, bosutinib and saracatinib, inhibited the global tyrosine phosphorylation as well as the basal auto-phosphorylation of SFKs. Mechanistically, inhibition of SFKs is coupled to apoptosis induction via decreased protein levels of the anti-apoptotic proteins Bcl-2, Mcl-1 and survivin, which were demonstrated by Western blotting. To assess apoptosis induction, annexin V binding to freshly isolated CLL cells with or without treatment with kinase inhibitors was measured flow cytometrically. Using the inhibitors at a concentration of 10 μM the average percentages of annexin V-positive, apoptotic cells in 11 CLL samples increased from 24 % in untreated controls to 55 %, 45 % and 37 % after treatment with bosutinib, saracatinib and dasatinib, respectively. The response to each of the inhibitors showed a high but comparable degree of variation among the investigated CLL samples. On the average bosutinib induced apoptosis with significantly higher efficiency than dasatinib, which calls for further investigation of its pre-clinical potential for treatment of CLL.
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Cheng, Keding. "Role of protein tyrosine phosphorylation in chronic lymphocytic leukemia cell apoptosis." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape4/PQDD_0016/MQ53138.pdf.
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Christodoulopoulos, Garyfallia. "Drug resistance to nitrogen mustards in B-cell chronic lymphocytic leukemia." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/nq64537.pdf.
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Weiss, David Michael. "Psychological Factors and Vaccine Immunity in Patients with Chronic Lymphocytic Leukemia." The Ohio State University, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=osu1575891774538146.
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Morrison, Eleshia JP. "Psychological Distress and Symptom Burden: Vulnerabilities in Chronic Lymphocytic Leukemia Patients." The Ohio State University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=osu1366305005.
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Dong, Shuai. "Pharmacologic and Genetic Investigation of PI3K p110delta in Chronic Lymphocytic Leukemia." The Ohio State University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=osu1503066319794882.
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Zucker, Mark Raymond. "Inferring Clonal Heterogeneity in Chronic Lymphocytic Leukemia From High-Throughput Data." The Ohio State University, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=osu1554049121307262.
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Merchand, Reyes Giovanna. "Targeting myeloid cells as a potential Chronic Lymphocytic Leukemia therapeutic strategy." The Ohio State University, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=osu1595259890785332.
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Favini, Chiara. "Biological and clinical implications of BIRC3 mutations in chronic lymphocytic leukemia." Doctoral thesis, Università del Piemonte Orientale, 2020. http://hdl.handle.net/11579/114875.
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The current shift of therapy of chronic lymphocytic leukemia (CLL) towards novel targeted agents mandates the identification of molecular predictors to inform on who can still benefit from chemoimmunotherapy and who can be instead early considered for novel targeted agents. Fludarabine, cyclophosphamide, and rituximab (FCR) is the most effective chemoimmunotherapy regimen for the management of CLL and represents the current standard of care for young and fit patients devoid of TP53 disruption. A retrospective multicenter cohort of 287 untreated patients receiving first-line FCR was analyzed by targeted next generation sequencing of 24 recurrently mutated genes in CLL. By univariate analysis adjusted for multiple comparisons BIRC3 mutations identify a poor prognostic subgroup of patients failing FCR (median progression free survival: 2.2 years, p < 0.001) similar to cases harboring TP53 mutations (median progression free survival: 2.6 years, p < 0.0001). BIRC3 mutations maintained an independent association with an increased risk of progression with a hazard ratio of 2.8 (95% confidence interval 1.4-5.6, p = 0.004) in multivariate analysis adjusted for TP53 mutation, 17p deletion and IGHV mutation status. The functional implications of BIRC3 mutations are largely unexplored and little is known about the prognostic impact of BIRC3 mutations in CLL cohorts homogeneously treated with first line FCR. By immunoblotting analysis, we showed that the non-canonical NF-kB pathway is active in BIRC3 mutated cell lines and in primary CLL samples, as documented by the stabilization of MAP3K14 and by the nuclear localization of p52. In addition, BIRC3 mutated primary CLL cells are less sensitive to fludarabine. If validated, BIRC3 mutations may be used as a new molecular predictor to select high-risk patients for novel frontline therapeutic approaches.
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CIARDULLO, CARMELA. "Clinical impact of small TP53 mutated subclones in chronic lymphocytic leukemia." Doctoral thesis, Università del Piemonte Orientale, 2015. http://hdl.handle.net/11579/115550.
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Willander, Kerstin. "Molecular genetic studies on Chronic Lymphocytic Leukemia and Acute Myeloid Leukemia - with focus on prognostic markers." Doctoral thesis, Linköpings universitet, Avdelningen för cellbiologi, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-104951.
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The present thesis is focused on the prognostic value of genetic variations and alterations in the initiation and development of chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML) patients. Several prognostic markers based on genetic or chromosomal aberrations are today used in clinic in these heterogeneous diseases. Novel biomarkers have been identified through next generation sequencing techniques and some of them may be useful as prognostic markers in clinical diagnostic. In papers I-IV we have investigated some of this markers in CLL and AML tumor cells. In papers I and III we investigated the prognostic value of the MDM2 SNP309 in relation to the presence of TP53 mutations in tumor cells from CLL and AML patients. The SNP309 G-allele was associated with a shorter overall survival in TP53 wildtype CLL and non-normal karyotype AML patients. Mutations in the TP53 gene were found in 6.2% in CLL and 21.7% in AML and were always associated with adverse overall survival. This was most significant observed among the AML patients, where the three year survival was zero. In paper II we investigated mutations in NOTCH1 and NOTCH2 as prognostic biomarkers in CLL. Notch1 and Notch2 play critical roles in lineage differentiation of white blood cells. We found mutation only in NOTCH1 in a frequency of 6.7% and our analysis revealed a shorter overall survival for these. NOTCH1 mutations were almost mutually exclusive with TP53 mutations and represented together 12.9% in CLL patients, and they may both be strong prognostic biomarkers in CLL. In paper IV we studied mutations in the tricarboxylic acid cycle. Metabolic disturbances in cancer cells have been known for many years, but recently mechanistic explanations have been identified. Hot spot mutations in IDH1/2 genes, result in neomorphic enzyme activities that results in global hypermethylation of the cancer cell genome. We found mutations in 21% of the AML patients. Among the CN-AML patients there is a lack of prognostic markers and in this subgroup we found patients with IDH2 mutations to have a shorter overall survival (3 vs. 21 months (p=0.009) for mutated and wild-type patients, respectively). Additionally, we also studied a SNP in the IDH1 gene, and both the IDH2 mutations and the SNP showed to have a potential as a new prognostic markers in CN-AML. In summary, the results in papers I-IV have a potential to function as novel prognostic biomarkers in the clinic for therapeutic considerations and may also be targets for novel drugs for CLL and AML patients.
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Wierz, Marina. "Characterization of the Tumor Microenvironment in Chronic Lymphocytic Leukemia by Mass Cytometry : Implications for Immunotherapy Dual PD1/LAG3 Immune Checkpoint Blockade Limits Tumor Development in a Murine Model of Chronic Lymphocytic Leukemia High-dimensional Mass Cytometry Analysis Revealed Microenvironment Complexity in Chronic Lymphocytic Leukemia." Thesis, université Paris-Saclay, 2020. http://www.theses.fr/2020UPASL020.
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La leucémie lymphoïde chronique (LLC), la leucémie la plus fréquente chez l'adulte, est caractérisée par l'accumulation de lymphocytes B matures dans le sang périphérique et les tissus lymphoïdes. La progression de la LLC est fortement dépendante des interactions complexes au sein du microenvironnement tumoral (TME) et malgré les récentes avancées dans le traitement de la LLC ciblant la TME, la LLC reste une maladie incurable. Par conséquent, nous voulions caractériser en profondeur le paysage immunitaire dans le TME dans la LLC murine et humaine afin d'identifier de nouvelles cibles potentielles pour une approche immunothérapeutique. À cette fin, nous avons effectué une caractérisation complète et approfondie par cytométrie de masse à haute dimension pour établir une cartographie approfondie des sous-populations de cellules immunitaires. Nous démontrons que les changements pertinents dans la composition des cellules immunitaires, en particulier l'expansion de sous-populations spécifiques de cellules immunitaires lymphoïdes et myéloïdes, sont associés à une forte suppression immunitaire contribuant ainsi à un phénotype d'échappement dans la LLC. Ces changements associés à la LLC peuvent être restaurés dans les modèles précliniques par un double blocage du point de contrôle immunitaire PD1/LAG3. De plus, nous démontrons une forte hétérogénéité des cellules T entre les patients qui peut être stratifiée en fonction de leur profil de cellules T, et la corrélation de sous-ensembles de cellules T spécifiques avec le temps jusqu'au traitement initial, mettant en évidence leur valeur pronostique potentielle. En conclusion, avec cette première étude CyTOF dans la LLC, nous avons élargi les connaissances actuelles sur la complexité phénotypique du TME. Nous avons démontré que le double ciblage des points de contrôle immunitaires contrôlait efficacement le développement de la LLC dans les modèles précliniques et pouvait donc avoir des avantages potentiels dans la LLC pour restaurer une immunité anti-tumorale fonctionnelleChronic lymphocytic leukemia (CLL), the most frequent leukemia in adults, is characterized by the accumulation of mature B lymphocytes in peripheral blood and lymphoid tissues. The progression of CLL is highly dependent on complex interactions within the tumor microenvironment (TME) and despite recent advances in CLL treatment targeting the TME, CLL remains an incurable disease. Therefore, we wanted to deeply characterize the immune landscape in the TME in murine and human CLL to identify novel potential targets for an immunotherapeutic approach. For this purpose, we performed a comprehensive and extensive characterization by high-dimensional mass cytometry to establish an extensive cartography of immune cell subsets. We demonstrated that relevant changes in the immune cell composition, especially the expansion of specific lymphoid and myeloid immune cell subsets, are associated with strong immune suppression thereby contributing to an escape phenotype in CLL. These CLL-associated changes can be restored in preclinical models by a dual PD1/LAG3 immune checkpoint blockade. Moreover, we demonstrated a high T cell heterogeneity between patients that can be stratified according to their T cell profile, and the correlation of specific T cell subsets with time to initial treatment, highlighting their potential prognostic value. In conclusion, with this first CyTOF study in CLL, we expanded the current knowledge of the phenotypic complexity of the TME. We demonstrated that dual targeting of immune checkpoints efficiently controlled CLL development in preclinical models and therefore could have potential benefits in CLL to restore a functional anti-tumor immunity
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Kwag, Doo Young. "Disease-specific complications of chronic lymphocytic leukemia in binet stage a patients." Diss., lmu, 2012. http://nbn-resolving.de/urn:nbn:de:bvb:19-150467.
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Halldórsdóttir, Anna Margrét. "Genetic and Epigenetic Profiling of Mantle Cell Lymphoma and Chronic Lymphocytic Leukemia." Doctoral thesis, Uppsala universitet, Hematologi och immunologi, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-156786.
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Mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) both belong to the group of mature B-cell malignancies. However, MCL is typically clinically aggressive while the clinical course of CLL varies. CLL can be divided into prognostic subgroups based on IGHV mutational status and into multiple subsets based on closely homologous (stereotyped) B-cell receptors. In paper I we investigated 31 MCL cases using high-density 250K single-nucleotide polymorphism arrays and gene expression arrays. Although most copy-number aberrations (CNAs) were previously reported in MCL, a novel deletion was identified at 20q (16%) containing the candidate tumor suppressor gene ZFP64. A high proliferation gene expression signature was associated with poor prognosis, large CNAs, 7p gains and 9q losses. Losses at 1p/8p/13q/17p were associated with increased genomic complexity. In paper II we sequenced exons 4 to 8 of the TP53 gene in 119 MCL cases. 17p copy-number status was known from previous studies or determined by real-time quantitative polymerase chain reaction. TP53 mutations were detected in 14% of cases and were strongly associated with poor survival while 17p deletions were more common (32%) but did not predict survival. In papers III and IV we applied high-resolution genomic 27K methylation arrays to 20 MCL and 39 CLL samples. In paper III MCL displayed a homogenous methylation profile without correlation with the proliferation signature whereas MCL was clearly separated from CLL. Gene ontology analysis revealed enrichment of developmental genes, in particular homeobox transcription factor genes, among targets methylated in MCL. In paper IV we compared three different stereotyped CLL subsets: #1 (IGHV unmutated), #2 (IGHV3-21) and #4 (IGHV mutated). Many genes were differentially methylated between each two subsets and immune response genes (e.g. CD80 and CD86) were enriched among genes methylated in subset #1 but not in subsets #2/#4. In summary, CNAs were frequent and not random in MCL. Specific CNAs correlated with a high proliferation gene expression signature or genomic complexity. TP53 mutations predicted short survival whereas 17p deletions did not. A high proliferation signature was not associated with differential DNA methylation in MCL, which demonstrated a homogeneous methylation pattern. In contrast, genomic methylation patterns differed between MCL and CLL and between stereotyped CLL subsets.
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Liu, Qing. "Targeting Protein Phosphatase 2a as a Therapeutic Strategy for Chronic Lymphocytic Leukemia." The Ohio State University, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=osu1213301219.
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Mao, Yicheng. "Monoclonal Antibody and Liposomal Nanoparticle-based Targeting Therapies for Chronic Lymphocytic Leukemia." The Ohio State University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=osu1354299911.
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Mohamed, Ahmed. "Deciphering the ontogeny of unmutated and mutated subsets of Chronic Lymphocytic Leukemia." Thesis, Högskolan i Skövde, Institutionen för biovetenskap, 2019. http://urn.kb.se/resolve?urn=urn:nbn:se:his:diva-17286.
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Chronic Lymphocytic Leukemia (CLL) is a type of cancer that affects the B cells of the immune system causing problems in the process of producing antibodies. It can be sorted into mutated and unmutated CLL based on the percentage of somatic mutations in the Immunoglobulin Heavy chain Variable region (IgHV). The B cells of healthy individuals can be sorted into three groups; CD27dull memory B cells (MBCs), CD27bright MBCs and naïve B cells. The hypothesis for the project was that the unmutated CLL subset originates from CD27dull MBCs and the mutated CLL subset originates from CD27bright MBCs. RNA-sequencing data from healthy individuals were acquired from a collaboration partner in Rome and CLL-patients were collected from public datasets available online. Several bioinformatic tools were used to analyze the data. First, the quality of the data files was checked, then adapter sequence from the sequencing process and low-quality bases were removed (trimming). Good quality of the files was confirmed after the trimming. Secondly, these files were mapped against the human reference genome (GRCh38/hg38) for alignment, then the resulted data was used to check for genes that showed differential expression between the different groups. Results were analyzed and visualized using Venn diagrams, Principal Component Analysis (PCA) and heatmap plots and random forest. A list of 85 genes was generated based on the different comparisons and was used in one PCA plot that showed clear separation between the different groups. The SWAP70 gene was analyzed for single nucleotide polymorphisms (SNPs). The study concluded five genes that could be used as biomarkers for CLL and the diagnosis of its subtypes where some of them were discussed in previous studies. Also, the mutated CLL subset showed a similar behavior to the healthy individuals and this could validate the original hypothesis and justifies the better disease prognosis for this subtype.
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Trimarco, Valentina. "Role of Nocodazole on the survival of chronic lymphocytic leukemia B cells." Doctoral thesis, Università degli studi di Padova, 2012. http://hdl.handle.net/11577/3422967.
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B-cell Chronic Lymphocytic Leukemia (B-CLL) is the most common leukemia in adults and is characterized by the accumulation of clonal CD19+/CD5+/CD23+ B lymphocytes, due to uncontrolled growth and resistance to apoptosis. Leukemic cells from B-CLL show reduced crosslink with specific molecules and high susceptibility to microtubule disrupting drugs, which suggest cytoskeletal alterations.
Microtubules play a crucial role in the vital functions of neoplastic cells, including mitosis, motility and cell-cell contact, and for this reason they became an important target in cancer therapies. In particular, tubulin, a cytoskeletal member, is the target of specific drugs, named microtubule inhibitors. Among these inhibitors, nocodazole induces tubulin depolimerization, mitotic process blocking and shows an apoptotic effect in B leukemic cells.
The aim of this study was to define the effects of nocodazole on B-CLL cells.
First of all, we verified nocodazole capability to favour the depolymerization of tubulin cytoskeleton in different cell types. In addition, we tested nocodazole-induced apoptosis in normal and leukemic B cells, in cell lines (Jurkat, Raji, and K562), in mesenchymal stromal cells (MSCs), and in T lymphocytes of B-CLL patients. Our data pointed out the high specificity of nocodazole for B-CLL cell apoptosis (leukemic cells: 57±25% vs normal B cells: 98±6%, p<0.0001; data are expressed as mean±standard deviation (SD) of percentage of viable cells after treatment with nocodazole) and the absence of toxicity to others cell types.
Growing evidence suggests that the marrow microenvironment, where MSCs are present, protects B-CLL cells from conventional anti-neoplastic drugs. The cultures of neoplastic B cells with MSCs and nocodazole demonstrated that nocodazole is able to overcome MSC protective effect, even after survival signal supplemental, such as CD40L or plasma from the same patients.
The action mechanism of nocodazole in B-CLL cells is still under investigation. However, we observed that nocodazole is able to turn off the increased basal tyrosine phosphorylation of leukemic cells mediated by Src-kinase Lyn through the down-modulation of Lyn active site. Since the specific inhibition of Lyn induces B-CLL cells apoptosis, this linking will be further investigated.
The results obtained in this study suggest a future role of nocodazole as a possible agent for treatment of B-CLL, for its extreme selectivity, the absence of toxicity and its ability to counteract the protective effect provided by marrow microenvironment.La Leucemia Linfatica Cronica di tipo B (LLC-B) è la forma più comune di leucemia nell’adulto ed è caratterizzata dall’accumulo clonale di piccoli linfociti B CD19+/CD5+/CD23+, dovuto sia ad una crescita incontrollata che ad una resistenza all’apoptosi. Le cellule leucemiche di LLC-B presentano inoltre alcune anomalie, come ridotta capacità di legare specifiche molecole e suscettibilità a farmaci che distruggono i microtubuli, che indicano la presenza di alterazioni a livello citoscheletrico. Il ruolo cruciale che i microtubuli rivestono nelle funzioni vitali delle cellule neoplastiche, quali mitosi, motilità e contatti cellula-cellula, li ha resi un importante target nelle terapie anti-tumorali. In particolar modo la tubulina, componente dei microtubuli, è il bersaglio di una categoria specifica di farmaci anti-tumorali, gli inibitori dei microtubuli; di questa famiglia fa parte anche il nocodazolo, un agente sintetico che induce la depolimerizzazione della tubulina, arresta il processo mitotico ed ha una peculiare specificità nell’indurre l’apoptosi nelle cellule B di LLC-B. Sulla base di queste considerazioni, abbiamo voluto approfondire gli effetti ed il meccanismo d’azione del nocodazolo sulle cellule di LLC-B. Dopo aver verificato che il nocodazolo sia effettivamente responsabile della depolimerizzazione dei filamenti di tubulina citoscheletrica in numerosi tipi cellulari, abbiamo valutato l’effetto apoptotico indotto dal nocodazolo in cellule B normali e di LLC-B, in linee cellulari (Jurkat, Raji e K562), in cellule stromali mesenchimali (MSC) e nei linfociti T residui di pazienti affetti da LLC-B. I risultati ottenuti evidenziano l’estrema selettività del nocodazolo nell’indurre l’apoptosi nelle sole cellule B di LLC-B (linfociti B di LLC-B: 57±25% vs B normali: 98±6%, p<0,0001; dati espressi come media±deviazione standard (DS) della percentuale di cellule vive dopo trattamento con nocodazolo) e l’assenza di tossicità nei confronti delle altre popolazioni cellulari prese in esame. Studi recenti suggeriscono che il microambiente midollare, in cui si trovano anche le MSC, sia in grado di proteggere le cellule leucemiche dall’azione dei farmaci chemioterapici convenzionali. La co-coltura di MSC e cellule B di LLC-B in presenza di nocodazolo ha dimostrato che tale inibitore è in grado di annullare l'effetto protettivo esercitato dalle MSC, nonostante la presenza di segnali di sopravvivenza quali CD40L o plasma ricavato dagli stessi pazienti. I meccanismi d’azione del nocodazolo rimangono ancora da chiarire, tuttavia abbiamo osservato come nelle cellule leucemiche di LLC-B il nocodazolo sia in grado di ridurre l’aumentata fosforilazione tirosinica basale mediata dalla Src-chinasi Lyn, mediante down-regolazione del sito attivatorio di Lyn. Dal momento che abbiamo dimostrato che l’inibizione specifica di Lyn induce apoptosi nelle cellule di LLC-B, questi primi risultati diventano rilevanti e dovranno essere ulteriormente indagati. In conclusione, i risultati ottenuti in questo studio hanno evidenziato l’estrema selettività del nocodazolo nell’indurre apoptosi nei linfociti B leucemici, l’assenza di tossicità in vitro e la capacità di contrastare l’effetto protettivo fornito dal microambiente midollare, suggerendo un futuro ruolo di questa sostanza quale possibile agente terapeutico per la cura della LLC-B.
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Bojnik, Engin. "Unlocking new molecular mechanisms and potential therapeutic targets for chronic lymphocytic leukemia." Doctoral thesis, Università degli studi di Padova, 2017. http://hdl.handle.net/11577/3422389.
Full textAbstract:
Chronic lymphocytic leukemia (CLL) represents the most common leukemia in the Western world. It is characterized by a neoplastic clonal expansion of CD5 B lymphocytes.
Deletion of the chromosomal 13q14 is the most frequent chromosomal aberration in CLL, but how it contributes to CLL pathogenesis and outcome of disease is still unclear. miR-15a and miR-16-1, located in the 13q14 region, are important for regulating levels of TP53 transcript and protein, As TP53 is a negative regulator of TERT, the catalytic component of telomerase, we hypotized that levels of TERT, are correlated with levels of miR-15a/16-1 and TP53. During first part of my PhD thesis, we characterized CLL cases, with the sole 13q14 deletion and with no chromosomal abnormalities, for miR-15a/16-1, TP53 and TERT expression. We found that levels of miR-15a and miR-16-1 were significantly lower in 13q14del CLL than in CLL with no chromosomal abnormalities and both miRNAs levels inversely correlated with TP53 expression. TERT levels inversely correlated with TP53 levels in 13q14del CLL, but not in CLL with normal cytogenetic profile and were significantly lower in the former group of CLL than in the latter one. Notably, disease progression was more rapid in both group of CLL with high TERT levels (>median), whereas high TP53 levels (>median) conferred better clinical outcome only in the subgroup of 13q14del CLL. Within the 13q14del CLL, TERT/ TP53 level profile identified subgroups of patients with different clinical outcomes. Within the 13q14del CLL, high TERT/low TP53 level profile is an independent marker of worse clinical outcome. Overall, these data indicate that in 13q14del CLL, the miR-15a/miR-16-1 and TP53 axis may be an important pathway regulating telomerase expression, and TERT/TP53 profile may be particularly useful in refining the prognosis of patients with 13q14del CLL.
Relevant proportion of CLL patients show biochemical and functional features of anergic B cells, characterized by the lack of signalling capacity and constitutive activation of ERK1/2. Anergy is the mechanisms that the immune system adopts to silence autoreactive B lymphocytes. Therefore, it is reasonable to suggest that reversing the anergic state of these CLL might be beneficial in terms of clinical responses.
The aim of my PhD studies, regarding search for new therapeutic strategies, was to evaluate the therapeutic potential of agents that target ERK activity in CLL, in vitro and in vivo. MEK1/2 inhibitor Trametinib was recently approved as a single-agent for the treatment of metastatic melanoma. During my stay at San Raffaele Institute, we preliminarily showed that in preclinical models (both in vitro and in vivo) a therapeutic effect can be observed when targeting the MAPK pathway, constitutively active in anergic B cells and in a subset of CLL patients. In particular, we showed that treatment with Trametinib significantly reduces the survival of a series of pERK(+) cell lines, human primary CLL and TCL1 mouse leukemic cells in vitro. We have also studied if Trametinib would potentiate the cytotoxic activity of BTK inhibitor Ibrutinib, both in vitro and in vivo, though with no success. Our data underscored the relevance of the anergic pathway as a potential therapeutic target in CLL.La leucemia linfatica cronica (LLC) rappresenta la leucemia più comune nel mondo occidentale. Essa è caratterizzata da una espansione clonale neoplastica di linfociti CD5 B. La delezione cromosomica 13q14 è l'aberrazione cromosomica più frequente nella LLC, ma come essa contribuisce alla patogenesi della LLC e l'esito della malattia è ancora poco chiaro. I miR-15a e miR-16-1, situati nella regione 13q14, sono importanti per la regolazione dei livelli di TP53, sia del trascritto sia della proteina. Essendo TP53 un regolatore negativo di TERT, il componente catalitico della telomerasi, abbiamo ipotizzato che i livelli di TERT sono correlati con i livelli di miR-15a / 16-1 e TP53. Durante la prima parte della mia tesi di dottorato, abbiamo caratterizzato i casi di LLC con la sola delezione 13q14 e senza anomalie cromosomiche, per l’espressione di miR-15a / 16-1, TP53 e TERT. Abbiamo scoperto che i livelli di miR-15a e miR-16-1 erano significativamente più bassi nei casi di LLC deleti rispetto ai casi di LLC senza anomalie cromosomiche. Inoltre i livelli di entrambi i miRNA erano inversamente correlati con l'espressione TP53. I livelli di TERT erano inversamente correlati con i livelli di TP53 solo nei casi 13q14del, ma non nei casi di LLC con il normale profilo citogenetico, e sono risultati significativamente più bassi nel primo gruppo di pazienti che in questi ultimi casi. In particolare, la progressione della malattia è stata più rapida in entrambi i gruppi di LLC con livelli di TERT elevati (> mediana), mentre i livelli TP53 elevati (> mediani) hanno conferito un migliore risultato clinico solo nel sottogruppo di 13q14del CLL. All'interno dei casi di LLC 13q14del, il profilo dei livelli di TERT/TP53 ha identificato sottogruppi di pazienti con differenti esiti clinici. In particolare in questo gruppo di pazienti il profilo costituito da alto livello di TERT / basso livello TP53 è un indicatore indipendente di un peggiore clinical outcome. Nel complesso questi dati indicano che nei casi di LLC con la delezione 13q14, il miR-15a / miR-16-1 e l'asse TP53 possono costituire un pathway importante che regola l'espressione della telomerasi; inoltre il profilo TERT può essere particolarmente utile nel perfezionare la prognosi dei pazienti affetti da leucemia linfocitica cronica 13q14del. Una proporzione rilevante di pazienti affetti da LLC mostra caratteristiche biochimiche e funzionali proprie delle cellule B anergiche, caratterizzate dalla mancanza di capacità e dall'attivazione costitutiva di ERK1/2. L’ anergia è un meccanismo che il sistema immunitario adotta per mettere a tacere i linfociti B autoreattivi. Pertanto, è ragionevole pensare che invertire lo stato anergico di questi LLC potrebbe essere vantaggioso in termini di risposta clinica. Lo scopo dei miei studi di dottorato, per quanto riguarda ricerca di nuove strategie terapeutiche, è stato quello di valutare il potenziale terapeutico di agenti che colpiscono l'attività di ERK nella LLC, sia in vitro sia in vivo. L’inibitore di MEK1/2 trametinib è stato recentemente approvato come singolo agente per il trattamento del melanoma metastatico. Durante il mio soggiorno al San Raffaele, abbiamo ottenuto dati preliminari che mostrano come attraverso il targeting del pathway di MAPK, costitutivamente attivo nelle cellule B anergiche, sia possibile ottenere un effetto terapeuticoe in modelli preclinici (sia in vitro sia in vivo) e in un sottogruppo di pazienti affetti da LLC. In particolare, abbiamo mostrato che il trattamento con trametinib riduce significativamente la sopravvivenza in vitro di una serie di linee cellulari pERK(+), di cellule primarie di LLC e di cellule leucemiche murine (TCL-1). Abbiamo anche studiato se trametinib sia in grado di potenziare l'attività citotossica dell’inibitore di BTK Ibrutinib, sia in vitro sia in vivo, ma senza successo. I nostri dati hanno sottolineato l'importanza del pathway dell’anergia come un potenziale target terapeutico nella LLC.