Articles de revues : « Leukemia cell »

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Abdel-Wahab, Omar, et Ross L. Levine. « Metabolism and the leukemic stem cell ». Journal of Experimental Medicine 207, n^o 4 (5 avril 2010) : 677–80. http://dx.doi.org/10.1084/jem.20100523.

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Acute leukemias are clonal disorders of hematopoiesis wherein a leukemic stem cell (LSC) acquires mutations that confer the capacity for unlimited self-renewal, impaired hematopoietic differentiation, and enhanced proliferation to the leukemic clone. Many recent advances in understanding the biology of leukemia have come from studies defining specific genetic and epigenetic abnormalities in leukemic cells. Three recent articles, however, further our understanding of leukemia biology by elucidating specific abnormalities in metabolic pathways in leukemic hematopoiesis. These studies potentially converge on the concept that modulation of reactive oxygen species (ROS) abundance may influence the pathogenesis and treatment of acute myeloid leukemia (AML).

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Ziegler-Heitbrock, HW, R. Munker, E. Thiel, I. Krebs et G. Riethmuller. « Killer cell activity of human monoblastic leukemia cells as detected with a monocyte-specific target cell ». Blood 65, n^o 1 (1 janvier 1985) : 8–14. http://dx.doi.org/10.1182/blood.v65.1.8.8.

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Abstract Peripheral blood leukemia cells from patients with acute monoblastic leukemia (AMoL) were tested for killer cell activity against target cells that detected natural killer cell-mediated or monocyte-mediated spontaneous cytotoxicity. The fibrosarcoma cell line Wehi 164, pretreated with actinomycin D to induce susceptibility to lysis, specifically detects the activity of unstimulated human monocytes. In four of six cases of AMoL, high killer cell activity could be measured against this target. In three of these four cases, the killer cell activity could be assigned exclusively to the leukemic clone, based on the high leukocyte counts and the resultant dilution of normal cells, as evidenced by marker and by functional analysis. While leukemic cells with killer cell activity against Wehi 164 contained 34% to 45% cells that were positive for binding of the 63D3 monoclonal antibody, the two leukemic samples without killer cell activity contained only 1% and 12% 63D3-positive cells. Cell sorting of 63D3-positive and -negative cells from two leukemias with killer cell activity demonstrated that the killer cell activity was restricted to the 63D3-positive fraction of AMoL cells. These data demonstrate that monoblastic leukemia cells can be potent killer cells and that killing activity is linked to the 63D3- defined cell surface molecule.

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Ziegler-Heitbrock, HW, R. Munker, E. Thiel, I. Krebs et G. Riethmuller. « Killer cell activity of human monoblastic leukemia cells as detected with a monocyte-specific target cell ». Blood 65, n^o 1 (1 janvier 1985) : 8–14. http://dx.doi.org/10.1182/blood.v65.1.8.bloodjournal6518.

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Peripheral blood leukemia cells from patients with acute monoblastic leukemia (AMoL) were tested for killer cell activity against target cells that detected natural killer cell-mediated or monocyte-mediated spontaneous cytotoxicity. The fibrosarcoma cell line Wehi 164, pretreated with actinomycin D to induce susceptibility to lysis, specifically detects the activity of unstimulated human monocytes. In four of six cases of AMoL, high killer cell activity could be measured against this target. In three of these four cases, the killer cell activity could be assigned exclusively to the leukemic clone, based on the high leukocyte counts and the resultant dilution of normal cells, as evidenced by marker and by functional analysis. While leukemic cells with killer cell activity against Wehi 164 contained 34% to 45% cells that were positive for binding of the 63D3 monoclonal antibody, the two leukemic samples without killer cell activity contained only 1% and 12% 63D3-positive cells. Cell sorting of 63D3-positive and -negative cells from two leukemias with killer cell activity demonstrated that the killer cell activity was restricted to the 63D3-positive fraction of AMoL cells. These data demonstrate that monoblastic leukemia cells can be potent killer cells and that killing activity is linked to the 63D3- defined cell surface molecule.

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I, Jamal. « Plasma Cell Leukemia : An Overview ». Haematology International Journal 5, n^o 1 (2021) : 1–2. http://dx.doi.org/10.23880/hij-16000175.

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Krivtsov, Andrei V., Amit U. Sinha, Matthew C. Stubbs, Andrew Kung et Scott Armstrong. « Cell of Origin Influences Leukemia Stem Cell Phenotype. » Blood 114, n^o 22 (20 novembre 2009) : 3459. http://dx.doi.org/10.1182/blood.v114.22.3459.3459.

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Abstract Abstract 3459 Poster Board III-347 MLL-fusion proteins can transform either hematopoietic stem cells (HSC) or granulocyte macrophage progenitors (GMP) into leukemia stem cells (LSC). However, the leukemogenic process in HSC may differ from that in GMP. We transduced HSC and GMP with MLL-AF9 or control retroviruses. Single-cell sorted MLL-AF9 expressing HSC or GMP could be serially replated for over 9 passages. Upon transplantation into syngeneic mice, 86.3% (n=22) of HSC:MLL-AF9 single cell derived clones (SCC) induced AML with a median latency of 61 days, while 33.3% of GMP:MLL-AF9 SCC induced AMLs with median latency of 100 days. Immunophenotype analysis of the resultant leukemias demonstrated that long-term repopulating HSC (LT-HSC) and GMP-derived leukemias were quite similar, with a GMP-like (LGMP) population enriched in LSC in both cases. Gene expression analysis demonstrated that globally the LGMP isolated from HSC derived AMLs (AML:HSC) and GMP derived AMLs (AML:GMP) were similar to each other but possessed specific genetic programs reminiscent of the cell of origin (HSC or GMP). For example Evi1, Jun, and Fos oncogenes were highly expressed in HSC and AML:HSC, but expressed at low level in GMP or AML:GMP. The genetic program that distinguished LGMP:HSC from LGMP:GMP was found to be enriched in hematopoietic stem cells compared to more differentiated myeloid progenitors and correlate with genetic programs in and human MLL-rearranged AML associated with a poor clinical outcome in two independent MLL-rearranged AML data sets. In order to directly assess differences in treatment response for leukemias derived from different cells of origin, we treated leukemic mice with a chemotherapeutic agent often used to treatment human AMLs. Treatment of leukemic mice with Etoposide reduced the spleen weights in mice transplanted with AML:HSC to a lesser extent (28%) than in mice transplanted with AML:GMP (88%). Altogether, these data indicate that cell of origin of AML can influence the genetic program of fully developed leukemia, and thus could account for some of the heterogeneity in human leukemias and perhaps outcome. Disclosures No relevant conflicts of interest to declare.

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Cardoso, Angelo A., J. Pedro Veiga, Paolo Ghia, Hernani M. Afonso, W. Nicholas Haining, Stephen E. Sallan et Lee M. Nadler. « Adoptive T-Cell Therapy for B-Cell Acute Lymphoblastic Leukemia : Preclinical Studies ». Blood 94, n^o 10 (15 novembre 1999) : 3531–40. http://dx.doi.org/10.1182/blood.v94.10.3531.422k14_3531_3540.

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We have previously shown that leukemia-specific cytotoxic T cells (CTL) can be generated from the bone marrow of most patients with B-cell precursor acute leukemias. If these antileukemia CTL are to be used for adoptive immunotherapy, they must have the capability to circulate, migrate through endothelium, home to the bone marrow, and, most importantly, lyse the leukemic cells in a leukemia-permissive bone marrow microenvironment. We demonstrate here that such antileukemia T-cell lines are overwhelmingly CD8+ and exhibit an activated phenotype. Using a transendothelial chemotaxis assay with human endothelial cells, we observed that these T cells can be recruited and transmigrate through vascular and bone marrow endothelium and that these transmigrated cells preserve their capacity to lyse leukemic cells. Additionally, these antileukemia T-cell lines are capable of adhering to autologous stromal cell layers. Finally, autologous antileukemia CTL specifically lyse leukemic cells even in the presence of autologous marrow stroma. Importantly, these antileukemia T-cell lines do not lyse autologous stromal cells. Thus, the capacity to generate anti–leukemia-specific T-cell lines coupled with the present findings that such cells can migrate, adhere, and function in the presence of the marrow microenvironment enable the development of clinical studies of adoptive transfer of antileukemia CTL for the treatment of ALL.

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Yan, Ying, Peter Steinherz, Xiuqin Guan, Ann Jakubowski, Joesph P. McGuirk et Richard J. O’Reilly. « Growth Potential of Human Leukemia Blast Cells in SCID Mice and Association with Prognosis of Human Acute Leukemias. » Blood 104, n^o 11 (16 novembre 2004) : 1900. http://dx.doi.org/10.1182/blood.v104.11.1900.1900.

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Abstract We have described a severe combined immunodeficiency (SCID) mouse model that permits the subcutaneous growth of primary human acute leukemia blast cells into a measurable subcutaneous nodule which may be followed by the development of disseminated disease. Utilizing the SCID mouse model, we examined the ability of patient-derived leukemic blasts to generate leukemic growth in the animals after subcutaneous inoculation without conditioning treatment. Leukemia blasts derived from 133 patients with acute leukemias, (67 acute lymphoblastic leukemia (ALL) and 66 acute myeloid leukemia (AML)), were inoculated into SCID mice. The leukemias displayed three distinct growth patterns: "aggressive", "indolent", or "no tumor growth". Out of 133 patients, leukemia samples 46 (34.5%) displayed an aggressive growth pattern, 14 (10.5%) indolent growth and 73 (55.0%) did not grow in SCID mice. The growth probability of leukemias from relapsed and/or refractory disease was 3 fold higher than that from patients with newly diagnosed disease. Serial observations found that leukemic blasts from the same individual, which did not initiate tumor growth at initial presentation and/or at early relapse, may engraft and grow in the later stages of disease, suggesting that the ability of leukemia cells for engraftment and proliferation was gradually acquired following the process of leukemia progression. Nine autonomous growing leukemia cell lines were established in vitro. These displayed an aggressive proliferation pattern, suggesting a possible correlation between the capacity of human leukemia cells for autonomous proliferation in vitro and an aggressive growth potential in SCID mice. It was demonstrated that patients whose leukemic blasts displayed an aggressive growth and dissemination pattern in SClD mice had a poor clinical outcome in patients with ALL as well as AML. Patients whose leukemic blasts grew indolently or whose leukemia cells failed to induce growth had a significantly longer DFS and more favorable clinical course.

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Tschanter, Petra, Nicole Baeumer, Lisa Lohmeyer, Frank Berkenfeld, Lara Tickenbrock, Sven Diederichs, Martin Stehling et al. « Loss of the Cell Cycle Regulator p26INCA1 Induces Exhaustion of Leukemic Stem Cells ». Blood 116, n^o 21 (19 novembre 2010) : 96. http://dx.doi.org/10.1182/blood.v116.21.96.96.

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Abstract Abstract 96 Acute myeloid leukemia is a clonal disease characterized by a malignant proliferation and accumulation of myeloid progenitor cells. Current therapeutic strategies are often not able to eradicate the leukemic cells. Malignancy is associated with deregulation of cell cycle check- points and the deregulation of checkpoints is associated with altered stem cell properties. A better understanding of malignant stem cells and their cell cycle regulation might help to develop new therapies. Recently, we identified p26INCA1 as a novel cell cycle regulator. GST pulldown assays revealed binding of INCA1 predominantly to CDK2- specific Cyclins and we demonstrated an inhibitory effect of INCA1 on CDK2/ CyclinA complexes in kinase activity assays. The loss of INCA1 and its inhibitory effect on the cell cycle regulation led to an increased cell cycling and consequently to an enlarged stem cell pool in vivo. Upon cytotoxic stress, the loss of Inca1 enhanced cell cycling and bone marrow exhaustion. To analyze a potential role of INCA1 in leukemogenesis we retrovirally transduced wildtype and Inca1−/− bone marrow cells with AML1-ETO9a (A1E9a) and transplanted these cells into wildtype recipients. Most of the wildtype cell- transplanted recipients died due to AML. In contrast, only one of the Inca1−/− cell- transplanted mice developed AML. Engraftment was higher upon transplantion of Inca1−/− cells but engraftment was not sustained. To consider the repopulation capacity of the leukemic cells we performed transplantation of primary leukemic cells into secondary recipients. A1E9a induced leukemia in Inca1 wildtype cells was transplantable and lethal. However Inca1−/− leukemic cells were severely impaired in leukemia development in secondary recipients. Colony forming units and replating capacity were significantly reduced in A1E9a Inca1−/− bone marrow cells although these cells showed increased CDK2 activity. Exhaustion of leukemic cells in the absence of Inca1 was confirmed by cloning efficiency assays. Further analyses were performed with c-myc induced leukemias. Interestingly, Inca1 deletion precluded the development of leukemias in secondary recipients. Taken together, these findings identify an important role for p26INCA1 in the maintenance of leukemia and potentially the self-renewal capacity of leukemic stem cells. Disclosures: No relevant conflicts of interest to declare.

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Gilliland, D. Gary, Craig T. Jordan et Carolyn A. Felix. « The Molecular Basis of Leukemia ». Hematology 2004, n^o 1 (1 janvier 2004) : 80–97. http://dx.doi.org/10.1182/asheducation-2004.1.80.

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Abstract Major strides have been made in our understanding of the molecular basis of adult and pediatric leukemias. More than one hundred disease alleles have been identified and characterized in cell culture and murine models of leukemia. In some instances, molecularly targeted therapies have been developed based on these insights that are currently in clinical trials, such as small molecule inhibitors of FLT3. In addition, it has recently been appreciated that, as with normal hematopoiesis, there is a hierarchical organization among leukemic cells that includes a rare population of leukemic stem cells that have properties of self-renewal. Understanding the characteristics of these leukemic stem cells may provide new insights into leukemia therapies that target self-renewal pathways. In Section I, Dr. Craig Jordan reviews the data that supports the existence of a “leukemia stem cell.” He provides an overview of the functional properties of leukemic stem cells, their relationship to hematopoietic stem cells, and the relevance of leukemic stem cells in other human malignancies including solid tumors. He briefly discusses what is known of the pathways that regulate properties of self-renewal. Dr. Gary Gilliland provides an overview of the genetics of adult leukemias in Section II and ongoing genome-wide strategies for discovery of new disease alleles. He describes the clinical and therapeutic implications of these findings and provides examples of bench-to-bedside translation of molecularly targeted therapies for AML, including the use of FLT3 inhibitors. In Section III, Dr. Carolyn Felix reviews recent advances in our understanding of the genetics and therapy of pediatric leukemias. She provides an overview of leukemias that are common in pediatric malignancies but rarely observed in adults, including the TEL-AML1 (ETV6-RUNX1) fusion associated with pediatric B-cell ALL, the OTT-MAL fusion associated with infant megakaryoblastic leukemia, PTPN11 mutations in juvenile myelomonocytic leukemia, and MLL fusion genes in leukemogenesis, among others.

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Swatler, Julian, Laura Turos-Korgul, Ewa Kozlowska et Katarzyna Piwocka. « Immunosuppressive Cell Subsets and Factors in Myeloid Leukemias ». Cancers 13, n^o 6 (10 mars 2021) : 1203. http://dx.doi.org/10.3390/cancers13061203.

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Both chronic myeloid leukemia and acute myeloid leukemia evade the immune response during their development and disease progression. As myeloid leukemia cells modify their bone marrow microenvironment, they lead to dysfunction of cytotoxic cells, such as CD8+ T cells or NK cells, simultaneously promoting development of immunosuppressive regulatory T cells and suppressive myeloid cells. This facilitates disease progression, spreading of leukemic blasts outside the bone marrow niche and therapy resistance. The following review focuses on main immunosuppressive features of myeloid leukemias. Firstly, factors derived directly from leukemic cells – inhibitory receptors, soluble factors and extracellular vesicles, are described. Further, we outline function, properties and origin of main immunosuppressive cells - regulatory T cells, myeloid derived suppressor cells and macrophages. Finally, we analyze interplay between recovery of effector immunity and therapeutic modalities, such as tyrosine kinase inhibitors and chemotherapy.

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Hudák, Renáta, Ildikó Beke Debreceni, Ivett Deák, Gabriella Gál Szabó, Zsuzsanna Hevessy, Péter Antal-Szalmás, Bjarne Osterud et János Kappelmayer. « Laboratory characterization of leukemic cell procoagulants ». Clinical Chemistry and Laboratory Medicine (CCLM) 55, n^o 8 (26 juillet 2017) : 1215–23. http://dx.doi.org/10.1515/cclm-2017-0021.

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Abstract Background: In acute myeloid leukemias, there is an increased chance to develop thrombotic disorders. We hypothesized that in addition to leukemic promyelocytes, monocytic leukemia cells may also have a higher procoagulant activity. Methods: Fibrin formation was assessed by a one-stage clotting assay using a magnetic coagulometer. The thrombin generation test (TGT) of magnetically isolated normal human monocytes, intact leukemic cells and their isolated microparticles was performed by a fluorimetric assay. Phosphatidylserine (PS) expression of leukemic cells and microparticle number determinations were carried out by flow cytometry. Results: All cell lines displayed a significant procoagulant potential compared to isolated normal human monocytes. In the TGT test, the mean of lagtime and the time to peak parameters were significantly shorter in leukemic cells (3.9–4.7 and 9.9–10.3 min) compared to monocytes (14.9 and 26.5 min). The mean of peak thrombin in various monocytic leukemia cell lines was 112.1–132.9 nM vs. 75.1 nM in monocytes; however, no significant difference was observed in the ETP parameter. Factor VII-deficient plasma abolished all procoagulant activity, whereas factor XII-deficient plasma did not affect the speed of fibrin formation and thrombin generation but modulated the amount of thrombin. Factor XI-deficient plasma affected the time to peak values in one leukemic cell line and also attenuated peak thrombin. Leukemia cell-derived microparticles from all three cell lines exerted a procoagulant effect by significantly shortening the lagtime in TGT; there was a nonsignificant difference in case of ETP parameter. Conclusions: All investigated monocytic leukemia cell lines exhibited significant thrombin generation. This phenomenon was achieved by the procoagulants on the surface of leukemic cells as well as by their microparticles.

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Liao, Aijun, Kathleen Broeg, Todd Fox, Su-Fern Tan, Rebecca Watters, Mithun Vinod Shah, Lucy Q. Zhang et al. « Therapeutic efficacy of FTY720 in a rat model of NK-cell leukemia ». Blood 118, n^o 10 (8 septembre 2011) : 2793–800. http://dx.doi.org/10.1182/blood-2011-01-331447.

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Abstract NK-cell leukemia is a clonal expansion of NK cells. The illness can occur in an aggressive or chronic form. We studied cell lines from human and rat NK-cell leukemias (aggressive NK-cell leukemia) as well as samples from patients with chronic NK-cell leukemia to investigate pathogenic mechanisms. Here we report that Mcl-1 was overexpressed in leukemic NK cells and that knockdown of Mcl-1 induced apoptosis in these leukemic cells. In vitro treatment of human and rat NK leukemia cells with FTY720 led to caspase-dependent apoptosis and decreased Mcl-1 expression in a time- and-dose-dependent manner. These biologic effects could be inhibited by blockade of reactive oxygen species generation and the lysosomal degradation pathway. Lipidomic analyses after FTY720 treatment demonstrated elevated levels of sphingosine, which mediated apoptosis of leukemic NK cells in vitro. Importantly, systemic administration of FTY720 induced complete remission in the syngeneic Fischer rat model of NK-cell leukemia. Therapeutic efficacy was associated with decreased expression of Mcl-1 in vivo. These data demonstrate that therapeutic benefit of FTY720 may result from both altered sphingolipid metabolism as well as enhanced degradation of a key component of survival signaling.

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Sohn, CC, DW Blayney, JL Misset, G. Mathe, G. Flandrin, EM Moran, FC Jensen, CD Winberg et H. Rappaport. « Leukopenic chronic T cell leukemia mimicking hairy cell leukemia : association with human retroviruses ». Blood 67, n^o 4 (1 avril 1986) : 949–56. http://dx.doi.org/10.1182/blood.v67.4.949.949.

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Abstract We report two cases of a T cell lymphoproliferative disease not previously described, with cytologic and clinical features similar to those associated with Galton's “prolymphocytic” leukemia (PL). Our patients, like those with Galton's PL, had massive splenomegaly and minimal or absent hepatomegaly and lymphadenopathy. In contrast, however, our patients had leukopenia, as well as low percentages of leukemic cells in the peripheral blood and in the bone marrow. In splenic imprints, the nuclear chromatin pattern of most of the leukemic cells was intermediate between those of mature lymphocytes and those of lymphoblasts, and the nuclei contained single, centrally located, conspicuous nucleoli. In sections of the spleen, the leukemic cells diffusely infiltrated the red pulp in a pattern strikingly similar to that of hairy cell leukemia; however, when the leukemic cells were studied cytochemically, the cytoplasmic acid phosphatase positivity was punctate and tartrate-sensitive. The leukemic cells were sheep erythrocyte rosette-positive and expressed T cell-associated antigens. Initially, both patients responded well to therapeutic splenectomy. One patient received combination chemotherapy after splenectomy and is alive and well 24 months after diagnosis. The other patient was in complete clinical remission for one year after splenectomy and received chemotherapy at relapse. He died, however, 23 months after splenectomy, with disseminated disease. IgG antibody titers against human T lymphotropic virus type I (HTLV-I) were detected in one patient and against HTLV-II in the other. The leukemia in these patients represents a distinct clinicopathologic entity within the spectrum of peripheral T cell lymphoproliferative diseases that includes Galton's PL of T cell derivation, T cell chronic lymphocytic leukemia, T cell hairy cell leukemia, and adult T cell leukemia/lymphoma.

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Sohn, CC, DW Blayney, JL Misset, G. Mathe, G. Flandrin, EM Moran, FC Jensen, CD Winberg et H. Rappaport. « Leukopenic chronic T cell leukemia mimicking hairy cell leukemia : association with human retroviruses ». Blood 67, n^o 4 (1 avril 1986) : 949–56. http://dx.doi.org/10.1182/blood.v67.4.949.bloodjournal674949.

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We report two cases of a T cell lymphoproliferative disease not previously described, with cytologic and clinical features similar to those associated with Galton's “prolymphocytic” leukemia (PL). Our patients, like those with Galton's PL, had massive splenomegaly and minimal or absent hepatomegaly and lymphadenopathy. In contrast, however, our patients had leukopenia, as well as low percentages of leukemic cells in the peripheral blood and in the bone marrow. In splenic imprints, the nuclear chromatin pattern of most of the leukemic cells was intermediate between those of mature lymphocytes and those of lymphoblasts, and the nuclei contained single, centrally located, conspicuous nucleoli. In sections of the spleen, the leukemic cells diffusely infiltrated the red pulp in a pattern strikingly similar to that of hairy cell leukemia; however, when the leukemic cells were studied cytochemically, the cytoplasmic acid phosphatase positivity was punctate and tartrate-sensitive. The leukemic cells were sheep erythrocyte rosette-positive and expressed T cell-associated antigens. Initially, both patients responded well to therapeutic splenectomy. One patient received combination chemotherapy after splenectomy and is alive and well 24 months after diagnosis. The other patient was in complete clinical remission for one year after splenectomy and received chemotherapy at relapse. He died, however, 23 months after splenectomy, with disseminated disease. IgG antibody titers against human T lymphotropic virus type I (HTLV-I) were detected in one patient and against HTLV-II in the other. The leukemia in these patients represents a distinct clinicopathologic entity within the spectrum of peripheral T cell lymphoproliferative diseases that includes Galton's PL of T cell derivation, T cell chronic lymphocytic leukemia, T cell hairy cell leukemia, and adult T cell leukemia/lymphoma.

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Chen, Changya, Wenbao Yu, Fatemeh Alikarami, Qi Qiu, Chia-hui Chen, Jennifer Flournoy, Peng Gao et al. « Single-cell multiomics reveals increased plasticity, resistant populations, and stem-cell–like blasts in KMT2A-rearranged leukemia ». Blood 139, n^o 14 (7 avril 2022) : 2198–211. http://dx.doi.org/10.1182/blood.2021013442.

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Abstract KMT2A-rearranged (KMT2A-r) infant acute lymphoblastic leukemia (ALL) is a devastating malignancy with a dismal outcome, and younger age at diagnosis is associated with increased risk of relapse. To discover age-specific differences and critical drivers that mediate poor outcome in KMT2A-r ALL, we subjected KMT2A-r leukemias and normal hematopoietic cells from patients of different ages to single-cell multiomics analyses. We uncovered the following critical new insights: leukemia cells from patients <6 months have significantly increased lineage plasticity. Steroid response pathways are downregulated in the most immature blasts from younger patients. We identify a hematopoietic stem and progenitor-like (HSPC-like) population in the blood of younger patients that contains leukemic blasts and form an immunosuppressive signaling circuit with cytotoxic lymphocytes. These observations offer a compelling explanation for the ability of leukemias in young patients to evade chemotherapy and immune-mediated control. Our analysis also revealed preexisting lymphomyeloid primed progenitors and myeloid blasts at initial diagnosis of B-ALL. Tracking of leukemic clones in 2 patients whose leukemia underwent a lineage switch documented the evolution of such clones into frank acute myeloid leukemia (AML). These findings provide critical insights into KMT2A-r ALL and have clinical implications for molecularly targeted and immunotherapy approaches. Beyond infant ALL, our study demonstrates the power of single-cell multiomics to detect tumor intrinsic and extrinsic factors affecting rare but critical subpopulations within a malignant population that ultimately determines patient outcome.

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Negi, Vijay, Liat Goldberg, Yang Jo Chung, Masahiro Onozawa et Peter D. Aplan. « Idh2R140Q Cooperates with NHD13 to Induce Immature T Cell Leukemia By Targeting Early T Cell Progenitors or DN2 Thymocytes ». Blood 134, Supplement_1 (13 novembre 2019) : 1346. http://dx.doi.org/10.1182/blood-2019-128675.

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Introduction Mutations in the isocitrate dehydrogenase 1 (IDH1) and IDH2 genes are frequently observed in patients with acute myeloid leukemia, with IDH2 mutations reported in 9- 19% of AML cases. IDH2 mutation leads to loss of normal enzymatic function and accumulation of 2-hydroxyglutarate (2-HG) through a newly gained enzyme activity. The most common IDH mutation in AML patients involves IDH2 R140. Transgenic mice that expressed an Idh2R140Q mutant in all hematopoietic tissues did not develop leukemia, nor was there a significant difference between overall survival of Idh2R140Q mice compared to wildtype mice. These findings were consistent with those from other investigators, which also suggested that expression of mutant IDH2 was not sufficient for development of leukemia, and that collaborating mutations are necessary. A recent report of whole exome sequence (WES) from mouse models of hematopoietic malignancies identified recurrent Idh1R132H mutations in NUP98-HOXD13 (NHD13) driven AML. Given that Idh1 R132 is paralogous to IDH2 R140, we considered the possibility that an Idh2R140Q mutation would collaborate with an NHD13 transgene and promote leukemic transformation. Therefore, we generated Idh2R140Q/NHD13 transgenic mice by crossing Idh2R140Q with NHD13 mice. Idh2R140Q/NHD13 transgenic mice developed a leukemia at a median of 10 months of age that was similar to human ETP in terms of immunophenotype and additional acquired cooperative mutations in genes such as Pten, N/Kras, Ptpn11, and Sh2b3. Results Gene set enrichment analysis (GSEA) based on RNA-Seq data from Idh2R140Q/NHD13 ETP leukemias and non-ETP T cell leukemias showed that Idh2R140Q/NHD13 ETP gene expression profile correlated well with human ETP leukemic expression profile. An in vitro thymocyte differentiation assay using co-culture of immature double negative (DN) 1 and DN2 thymocytes from Idh2R140Q/NHD13 mice on an OP9-DL1 stromal layer demonstrated a complete block in differentiation to double positive (DP) CD4+CD8+ thymocytes. The Idh2R140Q/NHD13 DN1/2 co-cultured cells arrested at the DN2 stage of differentiation, similar to the in-vivo phenotype of Idh2R140Q/NHD13 leukemia. In addition, Idh2R140Q/NHD13 DN1/2 cells had greater proliferative potential compared to wildtype control. We further observed that Idh2R140Q/NHD13 DN cells would proliferate indefinitely on OP9-DL1 stromal cells, and that treatment of Idh2R140Q/NHD13 thymocytes with AG-221, a potent and selective mutant IDH2 inhibitor, led to a marked decrease in cell proliferation. We developed an in vivo bone marrow transplantation (BMT) model for Idh2R140Q/NHD13 ETP leukemia to assess response to AG-221 in vivo. Primary Idh2R140Q/NHD13 ETP leukemia cells were transplanted into sub-lethally (600 cGy) irradiated recipient mice. This resulted in recipient mice that were anemic and thrombocytopenic with elevated white blood cell counts, suggesting engraftment of acute leukemia. The transplanted, secondary leukemias were consistent with the primary disease immunophenotype by flow cytometry, and tissue histology showed infiltration of blasts into the bone marrow, spleen and perivascular regions of the liver, consistent with disseminated leukemia. Blast cells were positive for both CD3 and myeloperoxidase, further highlighting an ETP phenotype. An assay for clonal T cell receptor beta rearrangement confirmed clonality of recipient leukemia cells identical to the primary leukemia cells. In vivo treatment of Idh2R140Q/NHD13 ETP recipient mice with AG221 showed a significant decrease in leukemic cell expansion compared to control mice treated by gavage with vehicle only; survival data is pending. Conclusion In summary, the IDH2 inhibitor data suggests that targeting the mutant IDH2 in Idh2R140Q/NHD13 leukemic cells can result in a significant decrease in leukemic burden in vivo. Furthermore, the Idh2R140Q/NHD13 primary ETP leukemia BMT mice serves as an excellent model for the study of ETP leukemia development and therapy. In this context, it is important to note that 14% of human ETP show mutations in IDH1/2, and although NUP98 translocations are rare but recurrent events in human ETP ALL, these NUP98 translocations lead to enforced expression of HOXA genes, which is a common event in ETP ALL. Disclosures Aplan: NIH: Patents & Royalties: royalties for the invention of NUP98-HOXD13 .

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Horton, Sarah J., Vanessa Walf-Vorderwülbecke, Steve J. Chatters, Neil J. Sebire, Jasper de Boer et Owen Williams. « Acute myeloid leukemia induced by MLL-ENL is cured by oncogene ablation despite acquisition of complex genetic abnormalities ». Blood 113, n^o 20 (14 mai 2009) : 4922–29. http://dx.doi.org/10.1182/blood-2008-07-170480.

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Abstract Chromosomal translocations involving 11q23 are frequent in infant acute leukemia and give rise to the formation of MLL fusion genes. The mechanism of leukemic transformation by these fusions has been the subject of numerous investigations. However, the dependence of acute leukemia on MLL fusion activity in vivo and the efficacy of targeting this activity to eliminate disease have not been established. We have developed a model for conditional expression of MLL-ENL in hematopoietic progenitor cells, in which expression of the fusion oncogene is turned off by doxycycline. Conditionally immortalized myeloblast cells derived from these progenitors were found to induce leukemia in vivo. Leukemic cells isolated from primary recipient mice were shown to have acquired additional genetic abnormalities and, when transplanted into secondary recipients, induced leukemia with shortened latencies. However, the leukemic cells remained dependent on MLL-ENL expression in vitro and in vivo, and its ablation resulted in regression of established leukemias. This study demonstrates that even genetically complex leukemias can be reversed on inactivation of the initiating MLL fusion and has important implications for the design of novel leukemia therapies.

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Morishita, H., H. Shiku, K. Horibe, Y. Obata, E. Stockert, H. F. Oettgen, L. J. Old et K. Yamada. « Cell surface antigens of murine leukemias induced by radiation leukemia virus. Recognition of individually distinct cell surface antigens by cytotoxic T cells on leukemias expressing crossreactive transplantation antigens. » Journal of Experimental Medicine 163, n^o 2 (1 février 1986) : 452–57. http://dx.doi.org/10.1084/jem.163.2.452.

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The specificity of transplantation immunity and T cell cytotoxicity against leukemias induced by RadLV was examined. Subcutaneous inoculation of two RadLV leukemias induced in BALB/c mice, BALBRVB and BALBRVD, resulted in initial tumor growth in CB6F1 mice, followed by complete tumor regression. Mice that had rejected leukemias BALBRVB or BALBRVD were subsequently challenged with various tumors of BALB/c origin. The growth of all five RadLV leukemias tested, and of one radiation-induced leukemia, was significantly inhibited. Another radiation-induced leukemia, a methylcholanthrene-induced sarcoma, and a leukemia induced by the Moloney leukemia virus, were not inhibited. The results indicate that RadLV leukemias share cell surface antigens that induce transplantation immunity in vivo. Cytotoxic lymphocytes were generated by coculturing spleen cells from mice that had rejected leukemia BALBRVB or BALBRVD with the corresponding leukemia cells. Direct tests and inhibition tests showed that such cytotoxic cells recognized individually specific antigens on leukemias BALBRVB and BALBRVD, distinct from the shared antigens detected in transplantation experiments. The effector cells in cytotoxicity assays were Thy-1+, Lyt-1+,-, Lyt-2+, and Lyt-3+ T cells.

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Harrer, Dennis C., Gerold Schuler, Jan Dörrie et Niels Schaft. « CSPG4-Specific CAR T Cells for High-Risk Childhood B Cell Precursor Leukemia ». International Journal of Molecular Sciences 20, n^o 11 (5 juin 2019) : 2764. http://dx.doi.org/10.3390/ijms20112764.

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The advent of CD19-specific chimeric antigen receptor (CAR) T cells has proven to be a powerful asset in the arsenal of cancer immunotherapy of acute lymphoblastic leukemia and certain B cell lymphomas. However, a sizable portion of patients treated with CD19-CAR T cells relapse with CD19-negative cancer cells, necessitating the quest for back-up antigens. Chondroitin sulfate proteoglycan 4 (CSPG4) expression has been reported on leukemic blasts bearing the ill-fated MLL 11q23 rearrangement. We aimed at exploring the use of CSPG4-specific CAR T cells against mixed-lineage leukemia (MLL)-rearranged leukemic blasts, using the precursor B cell leukemia cell line KOPN8 (MLL–MLLT1 translocation) as a model. First, we confirmed CSPG4 expression on KOPN8 cells. Bulk T cells electroporated with mRNA encoding a CSPG4-specific CAR upregulated activation markers and secreted the Th1 cytokines TNF and IFNγ in an antigen-specific manner upon co-culture with KOPN8 cells. More importantly, CSPG4-specific CAR T cells evinced specific degranulation towards KOPN8 cells and specifically lysed KOPN8 target cells in chromium lysis experiments. CSPG4 is a well-established CAR target in cutaneous melanoma. Here, we provide proof-of-principle data for the use of CSPG4-specific CAR T cells against MLL-translocated leukemias.

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Ling, Di, Ralph B. Arlinghaus et Xiaoyang Ling. « Vaccination with Leukemia Cell Expression Membrane Bound GM-CSF Overcomes the Host Immunosuppression Induced by Leukemia ». Blood 112, n^o 11 (16 novembre 2008) : 5435. http://dx.doi.org/10.1182/blood.v112.11.5435.5435.

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Abstract Immunotherapy of leukemia involves stimulating host-cell mediated immunity by facilitating immune recognition of leukemia cells, which are normally weakly immunogenic. We previously showed that vaccination with membrane bound GM-CSF leukemic cells protects mice from leukemia challenge (Ling et al., Oncogene, 2007). In these studies, after addition of a transmembrane domain to the original GM-CSF coding sequence (tmGM-CSF), the construct was transduced into murine leukemia cells (WEHI-3B), which was shown to be more than 98% on the cell surface. Vaccination with lethally irradiated tmGM-CSF expressing murine leukemia cells prevents leukemia in immunocompetent mice (BALB/c), as 100% of vaccinated BALB/c mice were protected from leukemia (Ling et al, Oncogene 2007). No protection was observed by vaccination of nude mice, indicating that adaptive immunity is involved in the protective response. In the present studies, we extended our original observation and provided evidence to show that leukemic mice undergo immunosuppression and that vaccination with leukemia cells expressing cell surface tmGM-CSF overcomes immunosuppression. Vaccination with lethally irradiated leukemia cells expressing cell surface tmGM-CSF overcame the immunosuppression induced by leukemia development, as normal levels of CD4+/CD25+/Foxp3+ T-regulatory (Treg) cells were maintained in spleens and thymus after challenge with leukemia cells. In contrast, the Treg population was significantly increased in leukemic mice vaccinated with leukemia cells lacking cell surface tmGM-CSF (p<0.001) after leukemia challenge, and these mice had a lower CD8+/Treg cell ratio (p<0.01). The ratio of CD8+/Treg cells was higher in tmGM-CSF/GFP vaccinated mice than in GFP vaccinated mice (p<0.001), which in-turn leads to a more effective CD8+ T-cell response. DC levels were also increased from normal levels in mice vaccinated with tmGM-CSF+ leukemia cells compared to control vaccinations. These results suggest that vaccination with leukemia cells expressing GM-CSF on their cell surface leads to an effective cell-mediated immune response in the vaccinated host by overcoming an impaired host cellular immunity induced up-regulation of Treg cells caused by the leukemia process. This strategy has potential for use in the treatment of various human leukemias.

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Shi, Yang, et Endi Wang. « Blastic Plasmacytoid Dendritic Cell Neoplasm : A Clinicopathologic Review ». Archives of Pathology & ; Laboratory Medicine 138, n^o 4 (1 avril 2014) : 564–69. http://dx.doi.org/10.5858/arpa.2013-0101-rs.

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Blastic plasmacytoid dendritic cell neoplasm is a rare entity grouped with the acute myeloid leukemia–related precursor neoplasms in the 2008 World Health Organization classification. It was previously postulated to originate from natural killer cells, T cells, or monocytes but is now believed to arise from the plasmacytoid dendritic cell. The pathogenesis of blastic plasmacytoid dendritic cell neoplasm is not well understood, although the neoplasm demonstrates frequent deletion of tumor suppressor genes, including RB1, CDKN1B, CDKN2A, and TP53. Blastic plasmacytoid dendritic cell neoplasm is a clinically aggressive tumor that often initially presents as cutaneous lesions and subsequently progresses to bone marrow involvement and leukemic dissemination. It is characterized by enhanced expression of CD56, CD4, and CD123, which can be detected by flow cytometry/immunohistochemistry. The differential diagnoses include myeloid sarcoma/acute myeloid leukemia, T-cell lymphoblastic leukemia/lymphoma, NK-cell lymphoma/leukemia, and some mature T-cell lymphomas/leukemias. Patients usually respond to initial chemotherapy but often relapse. Stem cell transplant may improve survival.

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Jones, RJ, SJ Sharkis, CB Miller, EK Rowinsky, PJ Burke et WS May. « Bryostatin 1, a unique biologic response modifier : anti-leukemic activity in vitro ». Blood 75, n^o 6 (15 mars 1990) : 1319–23. http://dx.doi.org/10.1182/blood.v75.6.1319.1319.

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Abstract Bryostatin 1, a macrocyclic lactone isolated from the marine bryozoan Bugula neritina, has demonstrated both antineoplastic activity against the murine P388 leukemia line in vivo and stimulatory activity against mouse and human hematopoietic progenitors. We studied the effects of bryostatin 1 on the growth of human leukemias in vitro. Bryostatin 1 inhibited 1 to 4 logs of clonogenic leukemia cell growth from three of four leukemia cell lines. Bryostatin 1 also inhibited, by at least 1 log, the proliferation of clonogenic acute nonlymphocytic leukemia (ANLL) cells from 10 to 12 patients with newly diagnosed or relapsed ANLL. Maximal inhibition of leukemic growth occurred at 10(-9) to 10(- 7) mol/L bryostatin 1. Interestingly, bryostatin 1 also inhibited the growth of hematopoietic progenitors from eight patients with myelodysplastic syndromes (MDS). Leukemia cells exposed to bryostatin 1 for up to 96 hours and then washed, demonstrated no substantial inhibition of clonogenic growth, indicating that the anti-leukemic effect of bryostatin 1 is cytostatic. The phorbol ester 12–0- tetradecanoylphorbol-13-acetate (TPA) produced more potent inhibition of clonogenic leukemia growth, and this inhibition was blocked by bryostatin 1. Thus, the anti-leukemic activity of bryostatin 1 may be mediated through activation of protein kinase C. Bryostatin 1 inhibits clonogenic leukemia cells at concentrations that stimulate normal hematopoietic progenitors. The differential effects of bryostatin 1 on normal and abnormal hematopoiesis suggest that bryostatin 1 may have value in the treatment of leukemias and MDS.

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Jones, RJ, SJ Sharkis, CB Miller, EK Rowinsky, PJ Burke et WS May. « Bryostatin 1, a unique biologic response modifier : anti-leukemic activity in vitro ». Blood 75, n^o 6 (15 mars 1990) : 1319–23. http://dx.doi.org/10.1182/blood.v75.6.1319.bloodjournal7561319.

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Bryostatin 1, a macrocyclic lactone isolated from the marine bryozoan Bugula neritina, has demonstrated both antineoplastic activity against the murine P388 leukemia line in vivo and stimulatory activity against mouse and human hematopoietic progenitors. We studied the effects of bryostatin 1 on the growth of human leukemias in vitro. Bryostatin 1 inhibited 1 to 4 logs of clonogenic leukemia cell growth from three of four leukemia cell lines. Bryostatin 1 also inhibited, by at least 1 log, the proliferation of clonogenic acute nonlymphocytic leukemia (ANLL) cells from 10 to 12 patients with newly diagnosed or relapsed ANLL. Maximal inhibition of leukemic growth occurred at 10(-9) to 10(- 7) mol/L bryostatin 1. Interestingly, bryostatin 1 also inhibited the growth of hematopoietic progenitors from eight patients with myelodysplastic syndromes (MDS). Leukemia cells exposed to bryostatin 1 for up to 96 hours and then washed, demonstrated no substantial inhibition of clonogenic growth, indicating that the anti-leukemic effect of bryostatin 1 is cytostatic. The phorbol ester 12–0- tetradecanoylphorbol-13-acetate (TPA) produced more potent inhibition of clonogenic leukemia growth, and this inhibition was blocked by bryostatin 1. Thus, the anti-leukemic activity of bryostatin 1 may be mediated through activation of protein kinase C. Bryostatin 1 inhibits clonogenic leukemia cells at concentrations that stimulate normal hematopoietic progenitors. The differential effects of bryostatin 1 on normal and abnormal hematopoiesis suggest that bryostatin 1 may have value in the treatment of leukemias and MDS.

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Dias, Sergio, Margaret Choy, Kari Alitalo et Shahin Rafii. « Vascular endothelial growth factor (VEGF)–C signaling through FLT-4 (VEGFR-3) mediates leukemic cell proliferation, survival, and resistance to chemotherapy ». Blood 99, n^o 6 (15 mars 2002) : 2179–84. http://dx.doi.org/10.1182/blood.v99.6.2179.

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Abstract Similar to solid tumors, growth of leukemias may also be angiogenesis dependent. Furthermore, tyrosine kinase receptors specific to endothelial cells are expressed on certain subsets of leukemias. We have previously demonstrated the existence of a VEGF/VEGFR-2 autocrine loop on leukemic cells that supports their growth and migration. Here, we demonstrate that in response to leukemia-derived proangiogenic and proinflammatory cytokines such as basic fibroblast growth factor and IL-1, endothelial cells release increasing amounts of another vascular endothelial growth factor (VEGF) family member, VEGF-C. In turn, interaction of VEGF-C with its receptor VEGFR-3 (FLT-4) promotes leukemia survival and proliferation. We demonstrate in 2 cell lines and 5 FLT-4+ leukemias that VEGF-C and a mutant form of the molecule that lacks the KDR-binding motif induce receptor phosphorylation, leukemia proliferation, and increased survival, as determined by increased Bcl-2/Bax ratios. Moreover, VEGF-C protected leukemic cells from the apoptotic effects of 3 chemotherapeutic agents. Because most leukemic cells release proangiogenic as well as proinflammatory cytokines, our data suggest that the generation of a novel paracrine angiogenic loop involving VEGF-C and FLT-4 may promote the survival of a subset of leukemias and protect them from chemotherapy-induced apoptosis. These results identify the VEGF-C/FLT-4 pathway as a novel therapeutic target for the treatment of subsets of acute leukemia.

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Lange, B., M. Valtieri, D. Santoli, D. Caracciolo, F. Mavilio, I. Gemperlein, C. Griffin, B. Emanuel, J. Finan et P. Nowell. « Growth factor requirements of childhood acute leukemia : establishment of GM-CSF-dependent cell lines ». Blood 70, n^o 1 (1 juillet 1987) : 192–99. http://dx.doi.org/10.1182/blood.v70.1.192.192.

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Abstract Eight permanent cell lines were established from cells of 50 consecutive patients with childhood acute leukemia. Three cell lines required growth factor-containing conditioned media. Analysis using blocking antisera and recombinant granulocytic macrophage (GM) colony- stimulating factor (CSF) identified GM-CSF as a growth factor required to establish the latter three cell lines and necessary for their continuous proliferation in chemically defined medium. Two of the GM- CSF-dependent cell lines were derived from patients with undifferentiated T- and a biphenotypic B-myelomonocytic leukemia, which suggests that GM-CSF might maintain proliferation of leukemias originating from immature progenitor cells. Cytogenetic analysis indicated that all established leukemic cell lines were aneuploid, with six lines containing chromosomal alterations related to those observed in the leukemic cells of the patient. Two patients did not have an abnormal clone identified in the marrow but did yield an aneuploid cell line. These studies indicate that GM-CSF-dependent leukemic cell lines can be established in a fraction of childhood leukemia. These cell lines lend themselves to studies aimed at the evaluation in vitro of the role of growth factors in controlling proliferation and differentiation of leukemic cells.

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Lange, B., M. Valtieri, D. Santoli, D. Caracciolo, F. Mavilio, I. Gemperlein, C. Griffin, B. Emanuel, J. Finan et P. Nowell. « Growth factor requirements of childhood acute leukemia : establishment of GM-CSF-dependent cell lines ». Blood 70, n^o 1 (1 juillet 1987) : 192–99. http://dx.doi.org/10.1182/blood.v70.1.192.bloodjournal701192.

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Eight permanent cell lines were established from cells of 50 consecutive patients with childhood acute leukemia. Three cell lines required growth factor-containing conditioned media. Analysis using blocking antisera and recombinant granulocytic macrophage (GM) colony- stimulating factor (CSF) identified GM-CSF as a growth factor required to establish the latter three cell lines and necessary for their continuous proliferation in chemically defined medium. Two of the GM- CSF-dependent cell lines were derived from patients with undifferentiated T- and a biphenotypic B-myelomonocytic leukemia, which suggests that GM-CSF might maintain proliferation of leukemias originating from immature progenitor cells. Cytogenetic analysis indicated that all established leukemic cell lines were aneuploid, with six lines containing chromosomal alterations related to those observed in the leukemic cells of the patient. Two patients did not have an abnormal clone identified in the marrow but did yield an aneuploid cell line. These studies indicate that GM-CSF-dependent leukemic cell lines can be established in a fraction of childhood leukemia. These cell lines lend themselves to studies aimed at the evaluation in vitro of the role of growth factors in controlling proliferation and differentiation of leukemic cells.

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Wu, Mark L., Hau C. Kwaan et Charles L. Goolsby. « Atypical Hairy Cell Leukemia ». Archives of Pathology & ; Laboratory Medicine 124, n^o 11 (1 novembre 2000) : 1710–13. http://dx.doi.org/10.5858/2000-124-1710-ahcl.

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Abstract The morphologic differential diagnosis of mature B-cell neoplasms with cytoplasmic projections includes splenic lymphoma with villous lymphocytes and hairy cell leukemia. Although the classification of hairy cell leukemia is not universally recognized, 3 variants have been described, namely, classic, variant, and Japanese variant, each of which has different clinical and immunophenotypic features. Classic hairy cell leukemia is virtually always CD11c+, CD25+, and CD103+. Variant and Japanese variant hairy cell leukemias are usually CD11c+, always CD25−, and occasionally CD103+. Each variant is characteristically CD10−. We present a case of hairy cell leukemia with a unique immunoprofile in that the cells were CD10+, CD25+, and CD103−, and we review the criteria helpful in differentiating “hairy” B-cell neoplasms. This case emphasizes the variability of hairy cell leukemia and the need to correlate all clinical and pathologic data in reaching a diagnosis.

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Cantilena, Caroline R., Xin Zhao, Sachiko Kajigaya, Neil Dunavin, Xin Tian, Stephen A. Strickland, Bipin N. Savani et al. « Activity of the Telomerase Inhibitor GRN163L (Imetelstat) on Acute Myeloblastic Leukemia Blasts Is Enhanced By DNA Methyltransferase Inhibitors Irrespective of TERT Promoter Methylation Status ». Blood 126, n^o 23 (3 décembre 2015) : 1267. http://dx.doi.org/10.1182/blood.v126.23.1267.1267.

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Abstract Introduction. The high telomerase activity in leukemia cells protects them from proliferation arrest, senescence, and apoptosis and may be driven by mutation or epigenetic alteration in the telomerase promoter. However, the mechanism of telomerase regulation and potential therapeutic application of telomerase inhibition in leukemia are not fully understood. We evaluated epigenetic methylation patterns in the telomerase promoter region in myeloid cell lines and primary acute myeloid leukemia (AML) blasts. These epigenetic patterns may serve as a biomarker for sensitivity to DNA methyltransferase (DNMT) inhibitors and have prognostic significance. We also studied whether the telomerase inhibitor GRN163L (imetelstat)can favorably combine with the DNMT inhibitor 5-Azacytidine (5-Aza) to target poor prognosis leukemias. Methods. We developed a pyrosequencing-based methylation assay to screen methylation profiles of the proximal promoter and partial exon 1 of the human telomerase reverse transcriptase (hTERT pro/Ex1) region in primary leukemic cells and various cell lines.We used a chemosensitivity assay to determine specific killing of primary leukemia and cell lines by imetelstat. An inert mismatched oligonucleotide (Geron Corporation, Menlo Park, CA, USA) was used to control for specific inhibition of the telomerase active site. Cells were cultured for 48 hours with either active imetelstat or the inert control at varying concentrations, stained with annexin-V and propidium iodide, and then analyzed by flow cytometry to measure cell viability, apoptosis, and necrosis. Results. The hTERT pro/Ex1 region was highly methylated in cell lines, relative to de novo primary leukemic cells. Primary leukemic cells showed significantly different methylation profiles and hypermethylation status correlated to poor survival of AML patients. Three commercially available leukemia cell lines (K562, Ramos, THP-1), two primary leukemia-derived cell lines (AML1, CML1), and CD34+ blasts isolated from primary leukemia in six different AML patients with varying degrees of hTERT pro/Ex1 region methylation were tested. Imetelstat showed dose dependent cytotoxicity to both myeloid leukemia cell lines and primary leukemic blasts. Cell toxicity was telomerase specific since the inert control had no or minimal toxicity at the half inhibitory concentration (IC50) of imetelstat between 10-40 µM. Higher methylation status of the hTERT pro/Ex1 region was significantly associated with increased resistance to imetelstat in leukemia cell lines (Figure 1A). However, no correlation was found in primary leukemic blasts. Pretreatment of leukemia cell lines with 5-Aza for 24 hours prior to imetelstat exposure was associated with a decrease in viability from 0.78±0.01 to 0.54±0.01 at a concentration of 10µM of imetelstat (Figure 1B). 5-Aza alone had no effect on the leukemic cell lines' viability. Conclusion. High risk primary leukemias are susceptible to killing by the telomerase inhibitor irrespective of the degree of methylation of the hTERT pro/Ex1 region. Furthermore, demethylating agents can enhance the activity of the telomerase inhibitor, imetelstat. These findings suggest that combination therapy of imetelstat and DNMT inhibitors may have synergistic anti-leukemic efficacy in high risk AML patients. Disclosures Strickland: Amgen: Other: Advisory Board Particpation; Boehringer-Ingelheim: Other: Advisory Board Particpation; Daiichi-Sankyo: Other: Advisory Board Particpation; Sunesis Pharmaceuticals: Other: Steering Committee and Advisory Board Participation; Alexion Pharmaceuticals: Other: Advisory Board Particpation. Rezvani:Pharmacyclics: Research Funding. Townsley:Novartis: Research Funding; GSK: Research Funding.

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Paiva, Aldair Sousa, Hugo Diogenes De Oliveira Paiva, Geraldo Barroso Cavalcanti, Lenilton Silva Silveira, Lorena KF Silva, Erica Aires Gil, Roberto C. Vasconcelos et al. « Contribution of Flow Cytometry Immunophenotyping in Diagnostic of Acute and Chronic Leukemias ». Blood 132, Supplement 1 (29 novembre 2018) : 5198. http://dx.doi.org/10.1182/blood-2018-99-118923.

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Abstract BACKGROUND: Today immunophenotyping by flow cytometry is an useful adjunct to cytomorphologyc analysis to correct diagnostic of leukemias. It provides objective and quantitative data allowing for a high level of sensitivity detection and better characterization of acute and chronic leukemias. The purpose of this study was to demonstrate the contribution of the immunophenotyping by monoclonal antibodies (Mo.Ab.) in leukemic cells from patients with acute and chronic leukemias. METHODS: Analyzed 76 patients with leukemias before the treatment. The diagnostic of leukemias was based on the morphological and immunophenotyping analysis of leukemic cells from peripheral blood and bone morrow. The cytomorphologycal analysis was based on French - American - Britsh criteria (FAB classification) in blood and bone marrow films stain by leishmann and the immunophenotyping by flow cytometry with a panel of Mo.Ab. specific to acute leukemias as: CD1a, CD2, CD3, CD4, CD5, CD8, CD7, CD10, CD13, CD19, CD20, CD103, CD22, CD33, CD34, CD117, CD38, HLADR, TdT, anti-mieloperoxidase, anti-IgM and anti-kappa and lambda light chain. Further clinical and laboratory information as age, sex, presence of tumoral mass, lymphadenopathy, hepatosplenomegaly, hemoglobin determination, total and specific white cell count and cytomorphological analysis of blood film and bone morrow smear. RESULTS: Thirty four patients presented acute myeloid leukemia (AML), twenty acute lymphoblastic leukemia (ALL), nineteen B-cell chronic lymphocytic leukemia (B-CLL), two T-cell chronic lymphocytic leukemia and one case was hairy cell leukemia (HCL). Males were more frequently found in all types of leukemias. ALL were more observed in children (age < 15 years old) and in AML however were more frequently in adults patients. The chronic leukemias were presented in patients with 50 years old or more in all cases. The correlation between the immunophenotyping and clinical pathological profile of these leukemias demonstrated that ALL were more associated to lymphadenopathy, AML to hepatosplenomegaly, and CLL to lymphadenopathy and high count of white cells in peripheral blood. The thrombocytopenia and anemia were found in more cases of acute leukemia. CONCLUSION: This date suggest that today the immunophenotyping by flow cytometry is an important methodology to diagnostic and classification of leukemias. Disclosures No relevant conflicts of interest to declare.

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Buss, Eike C., Alexander Kalinkovich, Amir Schajnovitz, Orit Kollet, Ayelet Dar, Melania Tesio, Stefan Fruehauf et al. « In Vivo Mobilization of Leukemic Human Precursor-B-ALL Cells by the CXCR4-Antagonist AMD3100 Is Via Secretion of SDF-1 and Synergistically by Catecholamine Action. » Blood 112, n^o 11 (16 novembre 2008) : 1920. http://dx.doi.org/10.1182/blood.v112.11.1920.1920.

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Abstract Introduction Mobilization of leukemic cells from the bone marrow (BM) to the circulation in order to better kill them with DNA damaging chemotherapy agents is emerging as a new experimental therapeutic intervention, however the mechanism is not entirely clear. Currently CXCR4-antagonists such as the mobilizing agent AMD3100 (AMD) are becoming available for clinical usage. The aim of this study is to explore mechanisms of human precursor-B-ALL cell mobilization from the BM in a functional, pre-clinical immune deficient mouse model. Methodology Immunodeficient mice were stably engrafted with the childhood pre-B-ALL leukemic cell line G2 (4 weeks after transplantation in NOD/SCID mice) and with primary childhood precursor-B-ALL cells from 4 patients (4-8 weeks after transplantation in NOD/SCID IL2R {gamma} null and NOD/SCID/B2m(null) mice). Two of the patients had a translocation (t4;11) (pro-B-ALL). All human leukemias were engrafted without prior irradiation of the mice. This approach prevents possible irradiation damage to the host microenvironment and thereby leads to a model which better mimics growth of human leukemias. To accommodate for differences in the level of leukemic BM engraftment (FACS analysis for huCD45+ cells), we assessed the leukemia mobilization level by calculating a leukemia mobilization index: WBC x % leukemic cells in the PB / % leukemic cells in the BM. Results and Discussion Treatment with AMD leads to a significant mobilization of all transplanted leukemias with a mobilization level of between 3 – 8 times above baseline. As we recently showed for mobilization of normal murine progenitors, AMD induces a strong release of SDF-1 from the BM (Dar et al. ASH 2006). To examine if this is also instrumental for the leukemia mobilization process, we inhibited SDF-1 action by injection of neutralizing CXCR4 antibodies (clone 12G5) in leukemic chimeras. This led to an abrogation of AMD-induced leukemia mobilization. Pointing towards the same mechanism, 3 daily injections of fucoidan, a known SDF-1 releasing agent, also led to significant leukemia mobilization in G2 and precursor-B-ALL chimeras. Recently we demonstrated that human hematopoietic stem and progenitor cells express receptors for catecholamines, such as dopamine and epinephrine (Epi) and that treatment with catecholamines leads to mobilization of murine progenitor cells (Spiegel et al. Nat. Immunol. 2007). Accordingly, we examined the effect of neurotransmitters. First, we found that the G2 cell line and all 4 examined precursor-BALL samples express the catecholamine receptors D3, D5 and beta-2. The expression is dynamic, as it was, in part, increased after engraftment of immunodeficient mice. Treatment of chimeras with high doses of Epi alone led to leukemia mobilization in vivo similar to AMD-induced mobilization. In combination with AMD, lower doses of norepinephrine increased leukemia obilization synergistically and significantly, resulting in dramatic leukemia mobilization up to 20 times above baseline. Unexpectedly and in contrast to normal cells, treatment of chimeras with the beta-2 agonist clenbuterol was accompanied by inhibition of AMD-induced mobilization of leukemic cells. These observations suggest similarities and differences in the activation of catecholamine receptors in the mobilization process of normal and leukemic cells. Conclusions Our results show that SDF-1 has a crucial role in AMD-induced leukemic cell mobilization. Human leukemias can be mobilized by catecholamine action synergistically with AMD in immunodeficient mice. This approach could be potentially used for future mobilization protocols of leukemia in combination with established chemotherapy to improve eradication of minimal residual disease of leukemia.

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Shvachko, L. P. « EMT-mechanizm induces the leukemic stemness phenotype in myeloid leukemias ». Faktori eksperimental'noi evolucii organizmiv 23 (9 septembre 2018) : 256–60. http://dx.doi.org/10.7124/feeo.v23.1024.

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Aim. To study the targeted expression EMT-induced markers N-cadherin, Snail and Twist in patients with the chronic and acute myeloid leukemias. Methods. RT-PCR, electroforesic in agarose gel, TotalLab v. 2.01 densitometry. Results. Have been investigated the relative levels of mRNA expression of N-cadherin and transcriptional factors Snail and Twist, associated with epithelial-to-mesenchymal induction (EMT) in patients with the essential polycytemia (EP), the chronic mieloid leukemia CML), the acute myeloid leukemia (AML) and the acute lymphoblastic leukemia (ALL). Conclusions. Have been highlighted the EMT stemness mechanism in Leukemic stem cell progression. Keywords: the epithelial-to-mesencymal transition (EMT), EMT-inducer marker, N-cadherin, Snail, Twist, myeloid leukemias, leuklemic stem cell progression.

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Rosen, Galit P., et Scott C. Kogan. « Acute Promyelocytic Leukemia Stem Cell Derived from Leukemic Progenitor. » Blood 108, n^o 11 (16 novembre 2006) : 235. http://dx.doi.org/10.1182/blood.v108.11.235.235.

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Efforts to identify the leukemic stem cell (or leukemia-repopulating cell, LRC) of acute myeloid leukemia (AML) have led to considerable insights, but also to a number of unresolved questions. While the LRC is believed to arise primarily from the hematopoietic stem cell, data from chronic myelogenous leukemia blast crisis and acute promyelocytic leukemia (APL) suggest that they may arise from more committed cells. In order to clarify the potential of committed progenitors to become LRCs in some human AMLs, we utilized the MRP8-PML/RARA transgenic murine model of APL to perform initial studies directed at the identification of the LRC in APL. Unsorted spleen cells of MRP8-PML/RARA leukemic mice injected into cohorts of sublethally irradiated mice using limiting dilutions showed that the LRC of APL is present in 1:100 to 1:300 cells. FACS analysis of six primary and serially transplanted leukemic specimens revealed that normal hematopoetic stem cells and myeloid progenitors were rare, comprising .007% and .078% of total splenic cells, respectively. These data raised the possibility that the LRC is present at higher frequency than these normal progenitors and does not belong to any of these populations. Given the scarcity of normal progenitors, we surmised that the LRC may be part of the leukemic population. We performed FACS analysis of seven primary leukemias to elucidate potential heterogeneity within the leukemic cell population. Myeloblasts had the immunophenotype lymph−Gr1+ckit+CD16/32+CD34mod/+. A smaller population that made up 1.4–12.7% of all cells was lymph−Gr1−ckitlo/mod and had variable expression of CD16/32 and CD34. Such cells have been identified as myelomonocytic cells and represent a stage in myelopoiesis beyond the GMP. Our findings suggest a hierarchy in which Gr1−ckitlo/mod leukemia repopulating cells proliferate and differentiate to maintain the population of abnormal promyelocytes. We infer from the dilution analysis data that the LRC in this MRP8-PML/RARA mouse model of acute promyelocytic leukemia cannot be a hematopoietic stem cell or a normal myeloid progenitor cell. Also, it is apparent that the entire blast population is not capable of transferring disease; otherwise, all the mice injected would have developed leukemia. While our data does indicate that while leukemogenesis in APL is a hierarchy, it originates from a newly identified leukemia progenitor cell that is Gr1−ckitlo/mod that may be more mature than a GMP. It is quite likely that the LRC lies within this population of cells. Future work will further delineate the immunophenotype of the LRC in this model and in human leukemia, as well as molecular abnormalities that are important in differentiating from the LRC into the myeloblast phenotype.

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Holden, JT, RB Geller, DC Farhi, HK Holland, LL Stempora, CN Phillips et RA Bray. « Characterization of Thy-1 (CDw90) expression in CD34+ acute leukemia ». Blood 86, n^o 1 (1 juillet 1995) : 60–65. http://dx.doi.org/10.1182/blood.v86.1.60.bloodjournal86160.

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Thy-1 (CDw90) is a phosphatidylinositol-anchored cell surface molecule which, when coexpressed with CD34 in normal human bone marrow, identifies a population of immature cells that includes putative hematopoietic stem cells. To date, the characterization of Thy-1 expression has been confined largely to normal tissues and cell lines. In this study, we evaluated the frequency and intensity of Thy-1 expression as defined by reactivity with the anti-Thy-1 antibody 5E10 in 38 cases of CD34+ acute leukemia (21 acute myelogenous leukemia [AML], 8 chronic myelogenous leukemia [CML] in blast crisis, and 9 acute lymphoblastic leukemia [ALL]). In 34 of 38 cases (89%) the CD34+ cells lacked expression of the Thy-1 antigen. High-density Thy-1 expression was found in 1 case of CML in lymphoid blast crisis, and low- density Thy-1 expression was identified on a portion of the leukemic cells in 2 cases of AML with myelodysplastic features, and 1 case of CML in myeloid blast crisis, suggesting a possible correlation between Thy-1 expression and certain instances of stem cell disorders such as CML and AML with dysplastic features. In contrast, the dissociation of Thy-1 and CD34 expression in the majority of acute leukemias studied suggests that the development of these leukemias occurs at a later stage than the hematopoietic stem cell. Characterization of Thy-1 expression in acute leukemia may eventually provide insights into the origin of the disease. In addition, separation of leukemic blasts from normal stem cells based on Thy-1 expression may prove useful in assessing residual disease, as well as in excluding leukemic blasts from stem cell preparations destined for autologous bone marrow or peripheral stem cell transplantation.

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Jacob, Bindya, Motomi Osato, Namiko Yamashita, Chelsia Qiuxia Wang, Ichiro Taniuchi, Dan R. Littman, Norio Asou et Yoshiaki Ito. « Stem cell exhaustion due to Runx1 deficiency is prevented by Evi5 activation in leukemogenesis ». Blood 115, n^o 8 (25 février 2010) : 1610–20. http://dx.doi.org/10.1182/blood-2009-07-232249.

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Abstract The RUNX1/AML1 gene is the most frequently mutated gene in human leukemia. Conditional deletion of Runx1 in adult mice results in an increase of hematopoietic stem cells (HSCs), which serve as target cells for leukemia; however, Runx1−/− mice do not develop spontaneous leukemia. Here we show that maintenance of Runx1−/− HSCs is compromised, progressively resulting in HSC exhaustion. In leukemia development, the stem cell exhaustion was rescued by additional genetic changes. Retroviral insertional mutagenesis revealed Evi5 activation as a cooperating genetic alteration and EVI5 overexpression indeed prevented Runx1−/− HSC exhaustion in mice. Moreover, EVI5 was frequently overexpressed in human RUNX1-related leukemias. These results provide insights into the mechanism for maintenance of pre-leukemic stem cells and may provide a novel direction for therapeutic applications.

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Takahashi, K., Y. Ohtsuki, H. Sonobe, K. Hayashi, S. Nakamura, S. Kotani, I. Kubonishi, I. Miyoshi, T. Isobe et K. Kita. « S-100 beta positive T cell leukemia ». Blood 71, n^o 5 (1 mai 1988) : 1299–303. http://dx.doi.org/10.1182/blood.v71.5.1299.1299.

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Abstract We reported a peculiar case with T cell leukemia. The patient was a 34- year-old woman showing extensive splenomegaly and marked leukemic cell proliferation and running a rapid fatal clinical course. The leukemic cells were morphologically ordinary lymphocytes showing suppressor/cytotoxic(s/c) T cell phenotypes and containing S-100b protein. Southern blot analysis revealed rearrangement of the beta chain genes of the T cell receptor (TcR) of the leukemic cells. Because these phenotypic and morphologic features were identical with those of S-100 beta+T lymphocytes (S-100 beta +TL) in normal human peripheral blood, we regarded this case as S-100 beta +T cell leukemia. We discussed clinicopathological features of S-100 beta +T cell leukemia/lymphoma by assessing similar cases reported so far. S-100 beta +T cell leukemia/lymphoma is a new type of s/c T lymphocytic leukemia/lymphoma with aggressive features.

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Takahashi, K., Y. Ohtsuki, H. Sonobe, K. Hayashi, S. Nakamura, S. Kotani, I. Kubonishi, I. Miyoshi, T. Isobe et K. Kita. « S-100 beta positive T cell leukemia ». Blood 71, n^o 5 (1 mai 1988) : 1299–303. http://dx.doi.org/10.1182/blood.v71.5.1299.bloodjournal7151299.

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We reported a peculiar case with T cell leukemia. The patient was a 34- year-old woman showing extensive splenomegaly and marked leukemic cell proliferation and running a rapid fatal clinical course. The leukemic cells were morphologically ordinary lymphocytes showing suppressor/cytotoxic(s/c) T cell phenotypes and containing S-100b protein. Southern blot analysis revealed rearrangement of the beta chain genes of the T cell receptor (TcR) of the leukemic cells. Because these phenotypic and morphologic features were identical with those of S-100 beta+T lymphocytes (S-100 beta +TL) in normal human peripheral blood, we regarded this case as S-100 beta +T cell leukemia. We discussed clinicopathological features of S-100 beta +T cell leukemia/lymphoma by assessing similar cases reported so far. S-100 beta +T cell leukemia/lymphoma is a new type of s/c T lymphocytic leukemia/lymphoma with aggressive features.

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Heltemes Harris, Lynn M., Gregory Hubbard, Rebecca LaRue, Sarah A. Munro, Rendong Yang, Christine Henzler, Aaron Sarver et Michael A. Farrar. « B cell transcription factors define a novel tumor suppressor gene network In ALL ». Journal of Immunology 204, n^o 1_Supplement (1 mai 2020) : 163.19. http://dx.doi.org/10.4049/jimmunol.204.supp.163.19.

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Abstract The transcription factors EBF1 and PAX5 are frequently mutated in B cell acute lymphoblastic leukemia (B-ALL). We demonstrated that Pax5+/− x Ebf1+/− compound heterozygous mice develop leukemia with high penetrance. Similar results were seen in Pax5+/− x Ikzf1+/− and Ebf1+/− x Ikzf1+/− mice for B-ALL, or in Tcf1+/− x Ikzf1+/− mice for T cell leukemia. To identify genetic defects that cooperate with Pax5 and Ebf1 compound heterozygosity to initiate leukemia, we carried out a Sleeping Beauty transposon screen. This screen identified a number of cooperating partners including gain-of-function mutations in Stat5 (~65%) and Jak1(~68%), as well as loss-of-function mutations in Cblb (61%)and Myb (32%). These findings highlight the key role of JAK/STAT5 signaling in cooperating with Pax5 and Ebf1 compound haploinsufficiency to drive B cell transformation. Moreover, these studies pointed to unexpected roles for loss of function mutations in CBL-b and MYB in B cell transformation. Subsequent RNA-Seq studies on WT, Pax5+/−, Ebf1+/−, Pax5+/− x Ebf1+/− pre-leukemic, Pax5+/− x Ebf1+/− leukemic cells and Pax5+/− x Ebf1+/− Sleeping Beauty leukemic cells demonstrated upregulation of a PDK1>PLK1>MYC pathway; treatment of Pax5+/− x Ebf1+/− leukemias with PDK1 specific inhibitors blocked their proliferation in vitro. Finally, we identified conserved transcriptional variation in a subset of genes between human leukemias and our mouse B-ALL models. Thus, compound haploinsufficiency for B cell transcription factors likely plays a critical role in transformation of human B cells and suggest that newly developed PDK1 inhibitors may be effective for treating patients characterized by such defects.

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Hanbali, Amr, Abdulaziz Alrajeh et Walid Rasheed. « Plasma cell leukemia mimicking hairy cell leukemia ». Hematology/Oncology and Stem Cell Therapy 8, n^o 2 (juin 2015) : 91–92. http://dx.doi.org/10.1016/j.hemonc.2015.05.001.

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Matulonis, UA, C. Dosiou, C. Lamont, GJ Freeman, P. Mauch, LM Nadler et JD Griffin. « Role of B7-1 in mediating an immune response to myeloid leukemia cells ». Blood 85, n^o 9 (1 mai 1995) : 2507–15. http://dx.doi.org/10.1182/blood.v85.9.2507.bloodjournal8592507.

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A costimulatory signal from B7–1 (CD80) to its counter-receptor CD28 is required for T-cell activation. Many tumors, including most human leukemias, lack expression of B7–1, and this has been suggested to contribute to the failure of immune recognition of these diseases. A murine leukemia model system was developed to assess the potential role of B7–1 in the induction immunity to leukemia cells. The nonleukemic 32Dc13 myeloid cell line was transformed by transfection of the BCR/ABL gene, generating a subline (32Dp210/clone 26) that was leukemic and rapidly lethal to syngeneic, immunocompetent C3H/HeJ mice or T-cell-deficient nude mice. B7–1-modified leukemic cells remained lethal in nude mice, but caused only a transient, nonlethal leukemia in C3H/HeJ mice. After a single exposure to live, nonirradiated B7–1-modified leukemic cells, C3H/HeJ mice developed protective immunity against subsequent challenge with B7–1(-) leukemic cells. Further, hyperimmunization with B7–1(+) leukemic cells prolonged the survival of mice previously injected with a lethal number of B7–1(-) leukemic cells. These results indicate that myeloid leukemic cells may be attractive candidates for B7–1 gene transfer.

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Kogan, Scott C., Suk-hyun Hong, David B. Shultz, Martin L. Privalsky et J. Michael Bishop. « Leukemia initiated by PMLRARα : the PML domain plays a critical role while retinoic acid–mediated transactivation is dispensable ». Blood 95, n^o 5 (1 mars 2000) : 1541–50. http://dx.doi.org/10.1182/blood.v95.5.1541.005k28_1541_1550.

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The most common chromosomal translocation in acute promyelocytic leukemia (APL), t15;17(q22;q21), creates PMLRAR andRARPML fusion genes. We previously developed a mouse model of APL by expressing PMLRAR in murine myeloid cells. In order to examine the mechanisms by which PMLRAR can initiate leukemia, we have now generated transgenic mice expressingPMLRARm4 and RARm4, proteins that are unable to activate transcription in response to retinoic acid.PMLRARm4 transgenic mice developed myeloid leukemia, demonstrating that transcriptional activation by PMLRAR is not required for leukemic transformation. The characteristics of the leukemias arising in the PMLRARm4 transgenic mice varied from those previously observed in our PMLRAR transgenic mice, indicating that ligand responsiveness may influence the phenotype of the leukemic cells. The leukemias that arose in PMLRARm4transgenic mice did not differentiate in response to retinoic acid therapy. This result supports the hypothesis that a major therapeutic effect of retinoic acid is mediated directly through thePMLRAR protein. However, a variable effect on survival suggested that this agent may be of some benefit in APL even when leukemic cells are resistant to its differentiative effects. Transgenic mice expressing high levels of RARm4 have not developed leukemia, providing evidence that the PML domain ofPMLRAR plays a specific and critical role in the pathogenesis of APL.

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Sumeet, Bajaj Preeti, Kasture Jyoti Uttamrao et Shah Balbir Singh. « Plasma Cell Leukemia : Clinicopathological Profile of Five Cases ». Indian Journal of Forensic Medicine and Pathology 9, n^o 3 (2016) : 189–91. http://dx.doi.org/10.21088/ijfmp.0974.3383.9316.18.

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Longo, Giuseppe S. A., Richard Gorlick, William P. Tong, Emine Ercikan et Joseph R. Bertino. « Disparate Affinities of Antifolates for Folylpolyglutamate Synthetase From Human Leukemia Cells ». Blood 90, n^o 3 (1 août 1997) : 1241–45. http://dx.doi.org/10.1182/blood.v90.3.1241.

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Abstract Previous work showed that acute myelocytic leukemia blasts accumulate less long chain polyglutamates of methotrexate (MTX) than acute lymphocytic leukemia blasts when incubated with this radiolabeled antifolate. This difference likely explains the increased sensitivity of lymphoid leukemias to short-term exposure of MTX as compared with myeloid leukemias. In this study, we examined the basis for differences between long chain MTX polyglutamate accumulation between different leukemia cell types using both leukemia cell lines and blasts freshly isolated from blood of leukemic patients. The major difference found between leukemia cells that accumulate long chain polyglutamates and those that do not were differences in Km values for the enzyme folylpolyglutamate synthetase. Km values did not change with partial purification of this enzyme, indicating that interfering substances in crude lysates were not responsible for this difference. We postulate that there may be differences in the properties of this enzyme related to tissue specific expression. In contrast to MTX, both Tomudex (Zeneca Pharmaceuticals, Wilmington, DE) and 1843U89, potent inhibitors of thymidylate synthetase, have low Kms for folylpolyglutamate synthetase, and polyglutamate forms of these inhibitors are accumulated to the same degree in both myeloid and lymphoid acute leukemia cells, paralleling the equivalent cytotoxicity found between myeloid and lymphoid leukemia cell lines. Based on these results, we believe a clinical trial of Tomudex in patients with acute myeloid leukemia is warranted.

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Longo, Giuseppe S. A., Richard Gorlick, William P. Tong, Emine Ercikan et Joseph R. Bertino. « Disparate Affinities of Antifolates for Folylpolyglutamate Synthetase From Human Leukemia Cells ». Blood 90, n^o 3 (1 août 1997) : 1241–45. http://dx.doi.org/10.1182/blood.v90.3.1241.1241_1241_1245.

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Previous work showed that acute myelocytic leukemia blasts accumulate less long chain polyglutamates of methotrexate (MTX) than acute lymphocytic leukemia blasts when incubated with this radiolabeled antifolate. This difference likely explains the increased sensitivity of lymphoid leukemias to short-term exposure of MTX as compared with myeloid leukemias. In this study, we examined the basis for differences between long chain MTX polyglutamate accumulation between different leukemia cell types using both leukemia cell lines and blasts freshly isolated from blood of leukemic patients. The major difference found between leukemia cells that accumulate long chain polyglutamates and those that do not were differences in Km values for the enzyme folylpolyglutamate synthetase. Km values did not change with partial purification of this enzyme, indicating that interfering substances in crude lysates were not responsible for this difference. We postulate that there may be differences in the properties of this enzyme related to tissue specific expression. In contrast to MTX, both Tomudex (Zeneca Pharmaceuticals, Wilmington, DE) and 1843U89, potent inhibitors of thymidylate synthetase, have low Kms for folylpolyglutamate synthetase, and polyglutamate forms of these inhibitors are accumulated to the same degree in both myeloid and lymphoid acute leukemia cells, paralleling the equivalent cytotoxicity found between myeloid and lymphoid leukemia cell lines. Based on these results, we believe a clinical trial of Tomudex in patients with acute myeloid leukemia is warranted.

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Pandey, Sony, Mustafa Moazam, Kurtis Eisermann, Jeffrey Hord, Gail Fraizer et Steven J. Kuerbitz. « The Importance of WT1 in Leukemia ». Blood 118, n^o 21 (18 novembre 2011) : 4645. http://dx.doi.org/10.1182/blood.v118.21.4645.4645.

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Abstract Abstract 4645 Acute leukemias collectively comprise the most common group of malignancies in the pediatric age group. Increasingly, therapeutic approach and prognosis are influenced by leukemia-specific cytogenetic abnormalities and genetic alterations, thus highlighting the importance of identifying novel prognostic markers. The Wilms’ tumor suppressor gene WT1 is expressed in leukemic blasts and is found to be mutated in approximately 10 percent of leukemia cases. Although it is unclear whether WT1 acts as an oncogene or a tumor suppressor gene in leukemia, it is known to regulate genes involved in cancer progression, including the angiogenic and mitogenic factor, VEGF. Previous studies in kidney and prostate cell lines identified potential WT1 binding sites on the VEGF-A gene promoter and demonstrated that WT1 transcriptionally regulated VEGF expression. Thus, we hypothesized that WT1 transcriptionally regulates VEGF expression in leukemia. To examine WT1 and VEGF expression patterns in pediatric Acute Lymphocytic Leukemia (ALL), Acute Myeloid Leukemia (AML) and non-neoplastic bone marrow samples, we performed quantitative real time PCR. It was observed that WT1 and VEGF expression varied depending upon the type and sub-type of leukemia. Furthermore, to understand the significance of WT1 expression, we over-expressed GFP- WT1 in Molt-4 cells (T-ALL), HL-60 (AML) and K562 cells (CML) and then quantified mRNA levels of VEGF and the potential WT1 target genes CCNA1 and JAG. The results showed that WT1 levels induced variable expression of VEGF, CCNA1 and JAG in these different leukemic cell lines. Elevated expression of WT1 genes harboring mutations of the zinc finger (ZF) DNA binding domain has also been described in a subset of leukemias and has been associated with a poor prognosis. We therefore screened pediatric acute leukemia samples for novel ZF mutations that would abrogate its ability to regulate VEGF and other target genes. Conversely, a well described SNP rs16754 (in exon 7 of the WT1 gene) identified as a good prognostic marker in Cytogenetically Normal AML (CN-AML) was observed in our pediatric population as both homozygous and heterozygous variants of the WT1 gene. Our long term goal is to determine the molecular basis of the prognostic impact associated with variant WT1 expression in pediatric and adult leukemias. Disclosures: No relevant conflicts of interest to declare.

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Quere, Ronan, Silja Andradottir, Ann Brun, Roman Zubarev, Göran Karlsson, Karin Olsson, Mattias Magnusson, Jörg Cammenga et Stefan Karlsson. « High Levels of the Adhesion Molecule CD44 on Leukemic Cells Generate Acute Myeloid Leukemia Relapse After Withdrawal of the Initial Transforming Event ». Blood 116, n^o 21 (19 novembre 2010) : 3154. http://dx.doi.org/10.1182/blood.v116.21.3154.3154.

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Abstract Abstract 3154 Multiple genetic hits are detected in patients with acute myeloid leukemia (AML). To investigate this further, we developed a tetracycline inducible mouse model of AML, where the initial transforming event, overexpression of HOXA10, can be eliminated. Continuous overexpression of HOXA10 is required to generate AML in primary recipient mice, but is not essential for maintenance of the leukemia. Transplantation of AML to secondary recipients showed that in established leukemias, ∼80% of the leukemia-initiating cells (LICs) in bone marrow stopped proliferating upon withdrawal of HOXA10 overexpression. However, the population of LICs in primary recipients is heterogeneous since ∼20% of the LICs induce leukemia in secondary recipients despite elimination of HOXA10 induced overexpression (HOXA10OFF). Since the withdrawal of the initial transforming event can be made upon demand, we have been able to ask what co-operating events are essential to maintain growth of leukemic cells as overexpression of HOXA10 is removed. Intrinsic genetic activation of several proto-oncogenes was observed in leukemic cells resistant to inactivation of the initial transformation event. We have identified a frequent increase in the activation of the proto-oncogenes JUN, FOS and EGR1 in relapsed leukemia where overexpression of HOXA10 has been withdrawn (HOXA10OFF versus HOXA10ON conditions). In order to further investigate if another possible mechanism is involved in leukemia, upon withdrawal of the primary oncogenic event, we performed proteomic analysis using mass spectrometry. Interestingly, we observed that upon removal of the primary event, leukemia that continued to grow produced high levels of several proteins involved in cell-cell and cell-matrix interactions. Among these proteins, CD44 is expressed on the cell surface and participates in cell transmigration and is an important target, since this surface glycoprotein mediates cell adhesion, migration and homing of hematopoietic cancer cells. To determine whether an increase in CD44 is a key mechanism by which LICs are resistant, we performed a functional test by FACS sorting leukemic cells generated in primary donors and transplanted 20,000 cells expressing different levels of the CD44 surface marker (CD44low, CD44medium and CD44high) in the tail vein of lethally irradiated secondary recipient mice fed doxycycline or ciproxine. When we monitored mice for occurrence of leukemia, outgrowth of leukemic cells was not dependant on the CD44 protein level on the HOXA10ON (doxycycline) condition. Consistent with this, onset of leukemia was not delayed for mice transplanted with CD44low leukemic cells. When mice were fed with ciproxine to turn off HOXA10 overexpression, all mice injected with CD44high leukemic cells developed leukemia, whereas all mice injected with CD44low leukemic cells remained healthy. In conclusion, we confirmed that withdrawal of the initial HOXA10 oncogene promotes the outgrowth of LICs expressing high levels of CD44. This study suggests that extrinsic niche-dependent factors are also involved in the host-dependent outgrowth of leukemias after withdrawal of HOXA10 overexpression event that initiates the leukemia. Here we demonstrate the highly aggressive nature of LICs expressing high levels of CD44 and conversely, show the impaired outgrowth of LICs expressing low levels of this surface marker. In conclusion, our murine model of inducible HOXA10 expression recapitulates many of the features of human AML and is helpful to analyse the “oncogene addiction” and unravel the basic mechanisms involved in initiation and maintenance of leukemia, and to study whether adhesion molecules expressed on the surface of leukemic cells are important factors for leukemic relapse in the microenvironmental niches of the bone marrow. Our findings support the notion that cell intrinsic genetic events are not the only factors causing leukemic relapse, but suggest that host-dependant extrinsic factors in the bone marrow niche may also play a fundamental role in the mechanism mediating leukemic relapse. Disclosures: No relevant conflicts of interest to declare.

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Ahuja, HG, PS Jat, A. Foti, M. Bar-Eli et MJ Cline. « Abnormalities of the retinoblastoma gene in the pathogenesis of acute leukemia ». Blood 78, n^o 12 (15 décembre 1991) : 3259–68. http://dx.doi.org/10.1182/blood.v78.12.3259.3259.

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Abstract The retinoblastoma-susceptibility (Rb) gene is an antioncogene that is frequently altered in retinoblastomas, sarcomas, and some epithelial tumors. We examined the structure of the Rb gene by Southern blotting in 215 cases of leukemias and lymphomas of diverse phenotype and in 15 leukemic cell lines. In selected cases Rb protein expression was examined with specific monoclonal antibodies. Structural abnormalities of the Rb gene with absent protein expression were frequent in all types of human acute leukemia, but were particularly common (27% incidence) in M4 and M5 myeloid leukemia with monocytic differentiation and in Philadelphia chromosome (Ph1)-positive leukemia of lymphoid phenotype (11% to 29% incidence). Changes in Rb were observed early in the transition to acute leukemia in cases of myelodysplastic syndrome and in the accelerated phase of chronic myelocytic leukemia in transition to blast crisis. In one case, molecular changes in Rb could be correlated with leukemia remission and relapse. We conclude that the Rb antioncogene is commonly involved in the evolution of human acute leukemias, particularly in those of a monocytic phenotype and in lymphoid leukemia in which there is an antecedent alteration of the Ph1 chromosome.

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Ahuja, HG, PS Jat, A. Foti, M. Bar-Eli et MJ Cline. « Abnormalities of the retinoblastoma gene in the pathogenesis of acute leukemia ». Blood 78, n^o 12 (15 décembre 1991) : 3259–68. http://dx.doi.org/10.1182/blood.v78.12.3259.bloodjournal78123259.

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The retinoblastoma-susceptibility (Rb) gene is an antioncogene that is frequently altered in retinoblastomas, sarcomas, and some epithelial tumors. We examined the structure of the Rb gene by Southern blotting in 215 cases of leukemias and lymphomas of diverse phenotype and in 15 leukemic cell lines. In selected cases Rb protein expression was examined with specific monoclonal antibodies. Structural abnormalities of the Rb gene with absent protein expression were frequent in all types of human acute leukemia, but were particularly common (27% incidence) in M4 and M5 myeloid leukemia with monocytic differentiation and in Philadelphia chromosome (Ph1)-positive leukemia of lymphoid phenotype (11% to 29% incidence). Changes in Rb were observed early in the transition to acute leukemia in cases of myelodysplastic syndrome and in the accelerated phase of chronic myelocytic leukemia in transition to blast crisis. In one case, molecular changes in Rb could be correlated with leukemia remission and relapse. We conclude that the Rb antioncogene is commonly involved in the evolution of human acute leukemias, particularly in those of a monocytic phenotype and in lymphoid leukemia in which there is an antecedent alteration of the Ph1 chromosome.

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Flynn, Catherine M., et Dan S. Kaufman. « Donor cell leukemia : insight into cancer stem cells and the stem cell niche ». Blood 109, n^o 7 (28 novembre 2006) : 2688–92. http://dx.doi.org/10.1182/blood-2006-07-021980.

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Abstract Donor cell leukemia (DCL) is a rare complication of hematopoietic cell transplantation (HCT). Its incidence has been reported between 0.12% and 5%, although the majority of cases are anecdotal. The mechanisms of leukemogenesis in DCL may be distinct from other types of leukemia. Possible causes of DCL include oncogenic alteration or premature aging of transplanted donor cells in an immunosuppressed person. Although many studies have recently better characterized leukemic stem cells, it is important to also consider that both intrinsic cell factors and external signals from the hematopoietic microenvironment govern the developmental fate of hematopoietic stem cells (HSCs). Therefore, in cases of DCL, alteration of the microenvironment after HCT may increase the likelihood that some progeny of normal HSCs become leukemic. This complex intercommunication between cells, growth factors, and cytokines in the hematopoietic microenvironment are critical to balance HSC self-renewal, proliferation, and differentiation. However, this homeostasis is likely perturbed in the development of DCL, allowing unique insight into the stimuli that regulate normal and potentially abnormal hematopoietic development. In this article, we discuss the possible pathogenesis of DCL, its association with stem cells, and its likely dependence on a less-supportive stem cell niche.

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Namikawa, R., R. Ueda et S. Kyoizumi. « Growth of human myeloid leukemias in the human marrow environment of SCID-hu mice ». Blood 82, n^o 8 (15 octobre 1993) : 2526–36. http://dx.doi.org/10.1182/blood.v82.8.2526.2526.

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Abstract It has been shown previously that multilineage human hematopoiesis is maintained within human fetal bone marrow (BM) fragments implanted into severe combined immunodeficient (SCID) mice. We describe here an application of this animal model, the SCID-hu mouse, to the study of human myeloid leukemias. BM cells from 8 patients with various types of myeloid leukemias were injected directly into human bone grafts in the SCID-hu mouse. Cells from 7 patients grew in the human marrow without spreading to the mouse marrow. Cells from 6 of these patients were successfully transferred in vivo to secondary SCID-hu recipients. The surface phenotype and the cytologic features of the leukemia cells were conserved during passage in vivo. Thus, human myeloid leukemia cells could be reproducibly propagated in the human marrow environment in SCID-hu mice. The differentiation of promyelocytic leukemia cells in the SCID-hu mice was induced by all-trans retinoic acid, suggesting that the biologic features of the leukemia cells were maintained as well. Finally, evidence for a leukemic progenitor cell population in one case of acute myelogenous leukemia was provided with this system. This model may provide a useful tool for studying the biology of human myeloid leukemia as well as for evaluating new therapeutic modalities for myeloid leukemias.

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Namikawa, R., R. Ueda et S. Kyoizumi. « Growth of human myeloid leukemias in the human marrow environment of SCID-hu mice ». Blood 82, n^o 8 (15 octobre 1993) : 2526–36. http://dx.doi.org/10.1182/blood.v82.8.2526.bloodjournal8282526.

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It has been shown previously that multilineage human hematopoiesis is maintained within human fetal bone marrow (BM) fragments implanted into severe combined immunodeficient (SCID) mice. We describe here an application of this animal model, the SCID-hu mouse, to the study of human myeloid leukemias. BM cells from 8 patients with various types of myeloid leukemias were injected directly into human bone grafts in the SCID-hu mouse. Cells from 7 patients grew in the human marrow without spreading to the mouse marrow. Cells from 6 of these patients were successfully transferred in vivo to secondary SCID-hu recipients. The surface phenotype and the cytologic features of the leukemia cells were conserved during passage in vivo. Thus, human myeloid leukemia cells could be reproducibly propagated in the human marrow environment in SCID-hu mice. The differentiation of promyelocytic leukemia cells in the SCID-hu mice was induced by all-trans retinoic acid, suggesting that the biologic features of the leukemia cells were maintained as well. Finally, evidence for a leukemic progenitor cell population in one case of acute myelogenous leukemia was provided with this system. This model may provide a useful tool for studying the biology of human myeloid leukemia as well as for evaluating new therapeutic modalities for myeloid leukemias.

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Articles de revues sur le sujet « Leukemia cell »

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