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Journal articles on the topic 'Leukemia'
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1
Yan, Ying, Peter Steinherz, Xiuqin Guan, Ann Jakubowski, Joesph P. McGuirk, and Richard J. O’Reilly. "Growth Potential of Human Leukemia Blast Cells in SCID Mice and Association with Prognosis of Human Acute Leukemias." Blood 104, no. 11 (November 16, 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.
2
Gilliland, D. Gary, Craig T. Jordan, and Carolyn A. Felix. "The Molecular Basis of Leukemia." Hematology 2004, no. 1 (January 1, 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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Horton, Sarah J., Vanessa Walf-Vorderwülbecke, Steve J. Chatters, Neil J. Sebire, Jasper de Boer, and Owen Williams. "Acute myeloid leukemia induced by MLL-ENL is cured by oncogene ablation despite acquisition of complex genetic abnormalities." Blood 113, no. 20 (May 14, 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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Abdel-Wahab, Omar, and Ross L. Levine. "Metabolism and the leukemic stem cell." Journal of Experimental Medicine 207, no. 4 (April 5, 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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Jones, RJ, SJ Sharkis, CB Miller, EK Rowinsky, PJ Burke, and WS May. "Bryostatin 1, a unique biologic response modifier: anti-leukemic activity in vitro." Blood 75, no. 6 (March 15, 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, and WS May. "Bryostatin 1, a unique biologic response modifier: anti-leukemic activity in vitro." Blood 75, no. 6 (March 15, 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, and 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, no. 6 (March 15, 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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Adamaki, Maria, Spiros Vlahopoulos, George I. Lambrou, Athanasios G. Papavassiliou, and Maria Moschovi. "Aberrant AML1 gene expression in the diagnosis of childhood leukemias not characterized by AML1-involved cytogenetic abnormalities." Tumor Biology 39, no. 3 (March 2017): 101042831769430. http://dx.doi.org/10.1177/1010428317694308.
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The AML1 ( acute myeloid leukemia 1) gene, a necessary prerequisite of embryonic hematopoiesis and a critical regulator of normal hematopoietic development, is one of the most frequently mutated genes in human leukemia, involving over 50 chromosome translocations and over 20 partner genes. In the few existing studies investigating AML1 gene expression in childhood leukemias, aberrant upregulation seems to specifically associate with AML1 translocations and amplifications. The aim of this study was to determine whether overexpression also extends to other leukemic subtypes than the ones karyotypically involving AML1. We use quantitative real-time polymerase chain reaction methodology to investigate gene expression in 100 children with acute leukemias and compare them to those of healthy controls. We show that in childhood acute lymphoblastic leukemia, AML1 gene overexpression is associated with a variety of leukemic subtypes, both immunophenotypically and cytogenetically. Statistically significantly higher transcripts of the gene were detected in the acute lymphoblastic leukemia group as compared to the acute myeloid leukemia group, where AML1 overexpression appeared to associate with cytogenetic abnormalities additional to those that engage the AML1 gene, or that are reported as showing a “normal” karyotype. Collectively, our study shows that AML1 gene overexpression characterizes a broader range of leukemic subtypes than previously thought, including various maturation stages of B-cell acute lymphoblastic leukemia and cytogenetic types additional to those involving the AML1 gene.
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Kogan, Scott C., Diane E. Brown, David B. Shultz, Bao-Tran H. Truong, Valerie Lallemand-Breitenbach, Marie-Claude Guillemin, Eric Lagasse, Irving L. Weissman, and J. Michael Bishop. "Bcl-2 Cooperates with Promyelocytic Leukemia Retinoic Acid Receptor α Chimeric Protein (Pmlrarα) to Block Neutrophil Differentiation and Initiate Acute Leukemia." Journal of Experimental Medicine 193, no. 4 (February 19, 2001): 531–44. http://dx.doi.org/10.1084/jem.193.4.531.
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The promyelocytic leukemia retinoic acid receptor α (PMLRARα) chimeric protein is associated with acute promyelocytic leukemia (APL). PMLRARα transgenic mice develop leukemia only after several months, suggesting that PMLRARα does not by itself confer a fully malignant phenotype. Suppression of apoptosis can have a central role in tumorigenesis; therefore, we assessed whether BCL-2 influenced the ability of PMLRARα to initiate leukemia. Evaluation of preleukemic animals showed that whereas PMLRARα alone modestly altered neutrophil maturation, the combination of PMLRARα and BCL-2 caused a marked accumulation of immature myeloid cells in bone marrow. Leukemias developed more rapidly in mice coexpressing PMLRARα and BCL-2 than in mice expressing PMLRARα alone, and all mice expressing both transgenes succumbed to leukemia by 7 mo. Although both preleukemic, doubly transgenic mice and leukemic animals had abundant promyelocytes in the bone marrow, only leukemic mice exhibited thrombocytopenia and dissemination of immature cells. Recurrent gain of chromosomes 7, 8, 10, and 15 and recurrent loss of chromosome 2 were identified in the leukemias. These chromosomal changes may be responsible for the suppression of normal hematopoiesis and dissemination characteristic of the acute leukemias. Our results indicate that genetic changes that inhibit apoptosis can cooperate with PMLRARα to initiate APL.
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Granados Romero, Francisco Fabian, and Enma maría Guadamud Lorenti. "Acute lymphoblastic leukemia." Journal of America health 1, no. 1 (January 2, 2018): 1–5. http://dx.doi.org/10.37958/jah.v1i1.1.
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Acute lymphoblastic leukemia is the most common hematologic neoplasm in pediatric age. Acute lymphoblastic leukemia (ALL) comprises 80% of all acute leukemias in this age group. Although the etiology is unknown, some genetic, viral and environmental predisposing factors have been detailed. The clinical manifestations are usually the result of bone marrow by leukemic cells (anemia, thrombopenia and neutropenia). The diagnosis is made by morphological, cytogenetic and molecular analysis of bone marrow aspirate. The treatment lasts about two years. The prognosis of children with acute lymphoblastic leukemia has improved brilliantly in recent decades thanks to new drugs and treatment tailored to patients' risk.
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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, no. 11 (November 16, 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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Swatler, Julian, Laura Turos-Korgul, Marta Brewinska-Olchowik, Sara De Biasi, Wioleta Dudka, Bac Viet Le, Agata Kominek, et al. "4-1BBL–containing leukemic extracellular vesicles promote immunosuppressive effector regulatory T cells." Blood Advances 6, no. 6 (March 17, 2022): 1879–94. http://dx.doi.org/10.1182/bloodadvances.2021006195.
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Abstract Chronic and acute myeloid leukemia evade immune system surveillance and induce immunosuppression by expanding proleukemic Foxp3+ regulatory T cells (Tregs). High levels of immunosuppressive Tregs predict inferior response to chemotherapy, leukemia relapse, and shorter survival. However, mechanisms that promote Tregs in myeloid leukemias remain largely unexplored. Here, we identify leukemic extracellular vesicles (EVs) as drivers of effector proleukemic Tregs. Using mouse model of leukemia-like disease, we found that Rab27a-dependent secretion of leukemic EVs promoted leukemia engraftment, which was associated with higher abundance of activated, immunosuppressive Tregs. Leukemic EVs attenuated mTOR-S6 and activated STAT5 signaling, as well as evoked significant transcriptomic changes in Tregs. We further identified specific effector signature of Tregs promoted by leukemic EVs. Leukemic EVs-driven Tregs were characterized by elevated expression of effector/tumor Treg markers CD39, CCR8, CD30, TNFR2, CCR4, TIGIT, and IL21R and included 2 distinct effector Treg (eTreg) subsets: CD30+CCR8hiTNFR2hi eTreg1 and CD39+TIGIThi eTreg2. Finally, we showed that costimulatory ligand 4-1BBL/CD137L, shuttled by leukemic EVs, promoted suppressive activity and effector phenotype of Tregs by regulating expression of receptors such as CD30 and TNFR2. Collectively, our work highlights the role of leukemic extracellular vesicles in stimulation of immunosuppressive Tregs and leukemia growth. We postulate that targeting of Rab27a-dependent secretion of leukemic EVs may be a viable therapeutic approach in myeloid neoplasms.
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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 (November 29, 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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Kogan, Scott C., Suk-hyun Hong, David B. Shultz, Martin L. Privalsky, and J. Michael Bishop. "Leukemia initiated by PMLRARα: the PML domain plays a critical role while retinoic acid–mediated transactivation is dispensable." Blood 95, no. 5 (March 1, 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 andRARPML 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 expressingPMLRARm4 and RARm4, proteins that are unable to activate transcription in response to retinoic acid.PMLRARm4 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 PMLRARm4 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 PMLRARm4transgenic 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 RARm4 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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Kettyle, Laura M., Charles-Étienne Lebert-Ghali, Ivan V. Grishagin, Glenda J. Dickson, Paul G. O’Reilly, David A. Simpson, Janet J. Bijl, Ken I. Mills, Guy Sauvageau, and Alexander Thompson. "Pathways, Processes, and Candidate Drugs Associated with a Hoxa Cluster-Dependency Model of Leukemia." Cancers 11, no. 12 (December 17, 2019): 2036. http://dx.doi.org/10.3390/cancers11122036.
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High expression of the HOXA cluster correlates with poor clinical outcome in acute myeloid leukemias, particularly those harboring rearrangements of the mixed-lineage-leukemia gene (MLLr). Whilst decreased HOXA expression acts as a readout for candidate experimental therapies, the necessity of the HOXA cluster for leukemia maintenance has not been fully explored. Primary leukemias were generated in hematopoietic stem/progenitor cells from Cre responsive transgenic mice for conditional deletion of the Hoxa locus. Hoxa deletion resulted in reduced proliferation and colony formation in which surviving leukemic cells retained at least one copy of the Hoxa cluster, indicating dependency. Comparative transcriptome analysis of Hoxa wild type and deleted leukemic cells identified a unique gene signature associated with key pathways including transcriptional mis-regulation in cancer, the Fanconi anemia pathway and cell cycle progression. Further bioinformatics analysis of the gene signature identified a number of candidate FDA-approved drugs for potential repurposing in high HOXA expressing cancers including MLLr leukemias. Together these findings support dependency for an MLLr leukemia on Hoxa expression and identified candidate drugs for further therapeutic evaluation.
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Shvachko, L. P. "EMT-mechanizm induces the leukemic stemness phenotype in myeloid leukemias." Faktori eksperimental'noi evolucii organizmiv 23 (September 9, 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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Santoro, E. Y., I. V. Kinchina, and V. I. Vetsega. "Leukemic optic disc infiltration in a patient with chronic myeloid leukemia: a clinical case." Modern technologies in ophtalmology, no. 1 (March 28, 2023): 354–57. http://dx.doi.org/10.25276/2312-4911-2023-1-354-357.
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Chronic myeloid leukemia is a malignant blood disease characterized by malignant transformation of hematopoetic progenitor cells, damage to the bone marrow, and other organs and systems. One of the rare manifestations of chronic myeloid leukemia is leukemiс infiltration of the optic disc. This process is characterized by damage to the optic nerve and nervous system by blast cells, which is an unfavorable prognosis for patients. It is important for an ophthalmologist to detect the disease and differentiate leukemic infiltration from other diseases accompanied by hemorrhages and optic disc edema. Timely diagnosis of the ophthalmologist and referral of the patient to the oncohematologist will allow early start of antitumor therapy. Keywords: leukemic optic disc infiltration, neuroleukemia, haemoblastosis, leukemia, ophthalmic symptoms
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Ahuja, HG, PS Jat, A. Foti, M. Bar-Eli, and MJ Cline. "Abnormalities of the retinoblastoma gene in the pathogenesis of acute leukemia." Blood 78, no. 12 (December 15, 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, and MJ Cline. "Abnormalities of the retinoblastoma gene in the pathogenesis of acute leukemia." Blood 78, no. 12 (December 15, 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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Namikawa, R., R. Ueda, and S. Kyoizumi. "Growth of human myeloid leukemias in the human marrow environment of SCID-hu mice." Blood 82, no. 8 (October 15, 1993): 2526–36. http://dx.doi.org/10.1182/blood.v82.8.2526.2526.
Full textAbstract:
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, and S. Kyoizumi. "Growth of human myeloid leukemias in the human marrow environment of SCID-hu mice." Blood 82, no. 8 (October 15, 1993): 2526–36. http://dx.doi.org/10.1182/blood.v82.8.2526.bloodjournal8282526.
Full textAbstract:
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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Heumann, D., G. Losa, C. Barras, A. Morell, and V. von Fliedner. "Characterization of acute undifferentiated leukemia by combined analysis of plasma membrane-associated gamma-glutamyltranspeptidase and soluble terminal transferase." Blood 66, no. 2 (August 1, 1985): 255–58. http://dx.doi.org/10.1182/blood.v66.2.255.bloodjournal662255.
Full textAbstract:
gamma-Glutamyltranspeptidase (gamma-GT) is a plasma membrane-associated enzyme present in blasts of certain acute leukemias. We analyzed 90 cases of undifferentiated and differentiated acute leukemias for gamma- GT, using a colorimetric assay. Blasts of all patients with common acute lymphoblastic leukemia (ALL) and T-ALL were negative for gamma-GT (less than 5 units). In contrast, gamma-GT was significantly elevated in acute myeloblastic or monoblastic leukemia blasts (P less than .001). In 16 cases of acute undifferentiated leukemia (AUL) studied, the levels of gamma-GT ranged from 0 to 93 units; in eight cases, gamma- GT was positive (greater than 5 units), and six of these had 2% to 5% Sudan black-positive leukemic cells in the blast-enriched suspension. Combined gamma-GT/TdT analysis revealed that both enzyme markers were mutually exclusive in 75% of AUL cases, suggesting that gamma-GT+/TdT- blasts are of nonlymphoid origin, and gamma-GT-/TdT+ blasts are of lymphoid origin. Two cases were devoid of both enzyme activities and could represent truly undifferentiated leukemia. Thus, combined gamma- GT/TdT analysis underlines the heterogeneity of AUL and appears to be useful in defining the lineage commitment of undifferentiated leukemic blasts.
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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, no. 10 (September 8, 2011): 2793–800. http://dx.doi.org/10.1182/blood-2011-01-331447.
Full textAbstract:
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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Pandey, Sony, Mustafa Moazam, Kurtis Eisermann, Jeffrey Hord, Gail Fraizer, and Steven J. Kuerbitz. "The Importance of WT1 in Leukemia." Blood 118, no. 21 (November 18, 2011): 4645. http://dx.doi.org/10.1182/blood.v118.21.4645.4645.
Full textAbstract:
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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Venugopalan, Radhika K., Neha Singh, Michael L. Anthony, Arathi Kunnumbrath, Arvind K. Gupta, Uttam K. Nath, Nilotpal Chowdhury, and Harish Chandra. "Leukemia-associated aberrant immunophenotype: A flow cytometry-based experience of 110 cases from a tertiary care center in Northern India." Journal of Cancer Research and Therapeutics 19, no. 5 (2023): 1335–39. http://dx.doi.org/10.4103/jcrt.jcrt_809_21.
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ABSTRACT Background: Leukemic cells express a characteristic set of “cluster of differentiation” (CD) markers, which forms the basis of the current WHO classification. Leukemia-associated aberrant immunophenotype (LAIP) refers to expression of unusual CD markers by leukemic cells, which are not normally expressed by their respective lineage. The incidence of LAIP varies considerably, and its clinical implications, prognostic relevance, and sensitivity to therapy are still debatable. This study was conducted to identify the immunophenotypic aberrancies in newly diagnosed leukemias in our Institute. Method: This was an observational study, which included newly diagnosed leukemias on flow cytometry. Aberrant immunophenotypic expressions were recorded whenever present and were correlated with prognostic factors like age, gender, and total leucocyte count (TLC). Results: The study included 110 newly diagnosed cases of leukemias (85 acute and 25 chronic) over 1.5 years. Immunophenotypic aberrancies were detected in 40.4% of the cases. The highest incidence of aberrations was detected in acute myeloid leukemia (60.7%). LAIPs were detected in 50% of T-acute lymphoblastic leukemia and 25% cases of in B-cell acute lymphoblastic leukemia (B-ALL). Aberrant CD33 and CD56 expression in B-ALL correlated with poor prognostic factors like higher age and higher TLC, respectively. Immunophenotypic aberrancies were present in 28% cases of chronic lymphocytic leukemia. Conclusion: The results of this study have generated valuable baseline data on the incidence of LAIPs in this region. This information is vital because establishing LAIPs at the time of diagnosis is crucial for disease monitoring. Some LAIPs are associated with underlying cytogenetic abnormalities and hence impact the management and prognosis.
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Bernt, Kathrin M., and Scott A. Armstrong. "Targeting Epigenetic Programs in MLL-Rearranged Leukemias." Hematology 2011, no. 1 (December 10, 2011): 354–60. http://dx.doi.org/10.1182/asheducation-2011.1.354.
Full textAbstract:
Abstract Rearrangements of the Mixed-Lineage Leukemia (MLL) gene are found in > 70% of infant leukemia, ∼ 10% of adult acute myelogenous leukemia (AML), and many cases of secondary acute leukemias. The presence of an MLL rearrangement generally confers a poor prognosis. There are more than 60 known fusion partners of MLL having some correlation with disease phenotype and prognosis. The most common fusion proteins induce the inappropriate expression of homeotic (Hox) genes, which, during normal hematopoiesis, are maintained by wild-type MLL. MLL-rearranged leukemias display remarkable genomic stability, with very few gains or losses of chromosomal regions. This may be explained by recent studies suggesting that MLL-rearranged leukemias are largely driven by epigenetic dysregulation. Several epigenetic regulators that modify DNA or histones have been implicated in MLL-fusion driven leukemogenesis, including DNA methylation, histone acetylation, and histone methylation. The histone methyltransferase DOT1L has emerged as an important mediator of MLL-fusion–mediated leukemic transformation. The clinical development of targeted inhibitors of these epigenetic regulators may therefore hold promise for the treatment of MLL-rearranged leukemia.
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Longo, Giuseppe S. A., Richard Gorlick, William P. Tong, Emine Ercikan, and Joseph R. Bertino. "Disparate Affinities of Antifolates for Folylpolyglutamate Synthetase From Human Leukemia Cells." Blood 90, no. 3 (August 1, 1997): 1241–45. http://dx.doi.org/10.1182/blood.v90.3.1241.
Full textAbstract:
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, and Joseph R. Bertino. "Disparate Affinities of Antifolates for Folylpolyglutamate Synthetase From Human Leukemia Cells." Blood 90, no. 3 (August 1, 1997): 1241–45. http://dx.doi.org/10.1182/blood.v90.3.1241.1241_1241_1245.
Full textAbstract:
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.
29
Tsuruta-Kishino, Takako, Keisuke Kataoka, Hiroshi Kobayashi, Junji Koya, Kensuke Narukawa, Tomohiko Sato, and Mineo Kurokawa. "Loss Of p53 Induces Leukemic Transformation In a Murine Model Of JAK2V617F-Induced Polycythemia Vera." Blood 122, no. 21 (November 15, 2013): 269. http://dx.doi.org/10.1182/blood.v122.21.269.269.
Full textAbstract:
Abstract Myeloproliferative neoplasms (MPN) have an inherent tendency toward leukemic transformation, but its mechanisms remain largely unknown. Recently, TP53 mutation is reported to be frequently found in cases with post-MPN leukemia. Here, to address the contribution of p53 loss to leukemic transformation from MPN in vivo, we retrovirally transduced c-kit+ bone marrow (BM) cells from p53 knockout (p53-/-) and littermate mice (p53+/+) with either wild-type Jak2 (Jak2WT) or Jak2V617F respectively, and transplanted them into lethally irradiated mice. At 3 weeks after transplantation, both recipients of Jak2V617F/p53-/- and Jak2V617F/p53+/+ cells developed a polycythemia vera-like disease characterized by high WBC count and elevated hemoglobin (Hb) level. Jak2V617F/p53+/+ mice survived and continued to have elevated Hb level, whereas 5 weeks after transplantation, Jak2V617F/p53-/- recipients developed cachexia, and their Hb level declined. Eventually, these mice developed fatal leukemia with a median survival of 46.5 days after transplantation, suggesting loss of p53 cooperates with Jak2V617F mutation to promote leukemic transformation from MPN. To characterize these leukemias, we analyzed leukemic tissues from moribund Jak2V617F/p53-/- mice. Peripheral blood smears and BM specimen from Jak2V617F/p53-/- recipients showed a marked increase of erythroid precursors with dysplastic features, leading to suppression of normal hematopoiesis. Notably, Jak2V617F/p53-/- mice displayed marked hepatosplenomegaly and extensive pulmonary hemorrhage. Consistent with the histopathologic findings, Jak2V617F/p53-/- animals exhibited a remarkable accumulation of erythroid precursors (CD71+), and especially more immature progenitors (Ter119-/CD71+) in the BM and spleen, compared with Jak2V617F/p53+/+ animals. These data suggest Jak2V617F/p53-/- recipients developed infiltrative disease with accumulation of immature erythroid cells, fulfilling the Bethesda Criteria of erythroleukemia in mice. To assess the transplantability of Jak2V617F/p53-/- leukemia, we injected unfractionated BM cells from Jak2V617F/p53-/- mice into lethally irradiated mice. In all cases, lethal leukemia developed earlier than in primary recipients. Moreover, there was a significant increase in erythroid progenitors in secondary recipients, suggesting the erythroid component is the predominant lineage involved in this leukemia model. As Jak2V617F/p53-/- leukemic tissues contained three major populations: CD71+ erythroid progenitors, Mac1+ mature myeloid cells, and lineage-negative (CD71-/Mac1-) primitive leukemic cells, we purified and transplanted these subfractions into secondary recipients to evaluate their leukemia-initiating potential. As a result, both lineage-negative (CD71-/Mac1-) cells and CD71+ erythroid progenitors possessed leukemia- initiating capacity, but Mac1+ myeloid cells could not reconstitute the disease. In addition, these two fractions had different capacities to induce leukemias; recipients of CD71+ cells rapidly developed erythroleukemia, whereas lineage-negative cells caused lethal leukemia after the polycythemic state. Moreover, hematopoietic tissues in recipients transplanted with CD71+ cells mainly consisted of erythroid lineages, whereas lineage-negative cells produced both erythroid and myeloid lineages, suggesting lineage-negative cells are more immature than CD71+ erythroid precursors. Furthermore, subsequent fractionation of lineage-negative cells revealed leukemia-initiating cells were enriched in Lin-/Sca-1+/c-kit+ (LSK) cells. To further characterize two types of leukemia-initiating cells in Jak2V617F/p53-/- leukemia, we assessed their sensitivity to a JAK2 inhibitor, INCB18424, in vitro. Interestingly, INCB18424 treatment significantly reduced CD71+ cell proliferation, whereas LSK cells were able to expand in the presence of INCB18424, indicating different leukemia-initiating cells existing in post-MPN leukemia have different responsiveness to JAK2 inhibiton. In summary, these results demonstrate p53 loss is sufficient for inducing leukemic transformation in JAK2V617F-postive MPN and offers an in vivo model to assess novel therapeutic approaches for post-MPN leukemia. In addition, we revealed leukemia-initiating cells at different differentiation stages could exist in post-MPN leukemia. Disclosures: Kurokawa: Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Consultancy, Research Funding.
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Heumann, D., G. Losa, C. Barras, A. Morell, and V. von Fliedner. "Characterization of acute undifferentiated leukemia by combined analysis of plasma membrane-associated gamma-glutamyltranspeptidase and soluble terminal transferase." Blood 66, no. 2 (August 1, 1985): 255–58. http://dx.doi.org/10.1182/blood.v66.2.255.255.
Full textAbstract:
Abstract gamma-Glutamyltranspeptidase (gamma-GT) is a plasma membrane-associated enzyme present in blasts of certain acute leukemias. We analyzed 90 cases of undifferentiated and differentiated acute leukemias for gamma- GT, using a colorimetric assay. Blasts of all patients with common acute lymphoblastic leukemia (ALL) and T-ALL were negative for gamma-GT (less than 5 units). In contrast, gamma-GT was significantly elevated in acute myeloblastic or monoblastic leukemia blasts (P less than .001). In 16 cases of acute undifferentiated leukemia (AUL) studied, the levels of gamma-GT ranged from 0 to 93 units; in eight cases, gamma- GT was positive (greater than 5 units), and six of these had 2% to 5% Sudan black-positive leukemic cells in the blast-enriched suspension. Combined gamma-GT/TdT analysis revealed that both enzyme markers were mutually exclusive in 75% of AUL cases, suggesting that gamma-GT+/TdT- blasts are of nonlymphoid origin, and gamma-GT-/TdT+ blasts are of lymphoid origin. Two cases were devoid of both enzyme activities and could represent truly undifferentiated leukemia. Thus, combined gamma- GT/TdT analysis underlines the heterogeneity of AUL and appears to be useful in defining the lineage commitment of undifferentiated leukemic blasts.
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Quere, Ronan, Silja Andradottir, Ann Brun, Roman Zubarev, Göran Karlsson, Karin Olsson, Mattias Magnusson, Jörg Cammenga, and 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, no. 21 (November 19, 2010): 3154. http://dx.doi.org/10.1182/blood.v116.21.3154.3154.
Full textAbstract:
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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Ling, Di, Ralph B. Arlinghaus, and Xiaoyang Ling. "Vaccination with Leukemia Cell Expression Membrane Bound GM-CSF Overcomes the Host Immunosuppression Induced by Leukemia." Blood 112, no. 11 (November 16, 2008): 5435. http://dx.doi.org/10.1182/blood.v112.11.5435.5435.
Full textAbstract:
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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Matulonis, UA, C. Dosiou, C. Lamont, GJ Freeman, P. Mauch, LM Nadler, and JD Griffin. "Role of B7-1 in mediating an immune response to myeloid leukemia cells." Blood 85, no. 9 (May 1, 1995): 2507–15. http://dx.doi.org/10.1182/blood.v85.9.2507.bloodjournal8592507.
Full textAbstract:
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.
34
Hosen, Naoki, Haruo Sugiyama, and Irving L. Weissman. "The Wilms’ Tumor Gene WT1 Is Over-Expressed in Immature Leukemia Cells but Not Necessary for Leukemia Development in Mouse Leukemia Models." Blood 108, no. 11 (November 16, 2006): 1429. http://dx.doi.org/10.1182/blood.v108.11.1429.1429.
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Abstract The Wilms tumor gene WT1, which is over-expressed in almost all leukemia, is one of the most promising targets for immunotherapy. To clarify which cells express WT1, we generated a knock-in reporter GFP mice (WT1GFP/+) and assayed for WT1 expression in normal and leukemic hematopoietic cells. In normal hematopoietic cells, WT1 was expressed in none of the long-term hematopoietic stem cells (HSCs) and very few (<1%) of multipotent progenitor cells. WT1 was expressed in 17.4% of megakaryocyte-erythrocyte progenitor cells and 4.1% of common myeloid progenitor cells, while the frequencies of WT1 expressing cells in mature granulocyte or lymphocyte were very low (~1%). In contrast, in murine leukemias induced by TEL/PDGFβR + AML1/ETO or BCR/ABL, WT1 was expressed in 40.5% or 38.9% of c-kit+lin-Sca-1+ (KLS) leukemia cells, which contained a subset, but not all, of transplantable leukemic stem cells (LSC). Furthermore, WT1 was not expressed fetal liver HSC population, mobilized HSCs by cyclophosphamide and granulocyte-colony stimulating factor, or HSCs stimulated with SCF, Flt3L, and IL3 in-vitro. These results suggest that WT1 expression in is not a surrogate marker of cell proliferation. To examine the function of WT1 in leukemogenesis, we used recombinant lentivirus to overexpress WT1. HSCs transduced with either empty or WT1-expressing lentivirus were transplanted into lethally irradiated recipients. The FACS analysis of BM cells at 4 months post transplant showed very low chimerism of WT1-expressing cells compared to control GFP-expressing cells. Moreover, differentiation block of WT1-expressing cells was not observed. These results indicate that WT1 does not induce proliferation or block differentiation in-vivo. Next, we tested whether leukemias could be induced from the WT1-deficient fetal liver hematopoietic cells. All of three mice transplanted with E13.5 WT1-defeicient fetal liver cells transduced with TEL/PDGFβR+AML1/ETO developed leukemia. Similarly, 3 out of 4 mice transplanted with p210BCR/ABL-transduced WT1-deficient fetal liver cells developed leukemia. These results indicate that WT1 is not necessary for leukemia development in two leukemia models examined. Collectively, WT1 is expressed on immature leukemic cells but not normal HSCs, highlighting its potential as a specific target for therapy. However, the exact function of WT1 in leukemogenesis remains unclear from these studies.
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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, no. 23 (December 3, 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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Gobessi, Stefania, Francesca Belfiore, Sara Bennardo, Brendan Doe, Luca Laurenti, and Dimitar G. Efremov. "Expression of ZAP-70 Does Not Accelerate Leukemia Development and Progression in the Eμ-TCL1 Transgenic Mouse Model of Chronic Lymphocytic Leukemia." Blood 120, no. 21 (November 16, 2012): 925. http://dx.doi.org/10.1182/blood.v120.21.925.925.
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Abstract Abstract 925 One of the most relevant prognostic factors in chronic lymphocytic leukemia (CLL) is expression of the protein tyrosine kinase ZAP-70. Typically, patients whose leukemic cells express ZAP-70 at 30–100% of the levels in normal T cells have aggressive disease, whereas patients whose leukemic cells do not express ZAP-70 or express only low levels of this protein have indolent disease. Previously, we and others demonstrated that ZAP-70 modulates B-cell receptor signaling and thus affects the capacity of the leukemic cells to respond to antigen stimulation. However, a direct link between an altered antigen response and CLL pathogenesis has still not been established and, more importantly, the question whether ZAP-70 directly contributes to the aggressiveness of the disease or is just a marker of aggressive CLL still remains to be answered. We have now addressed these issues by analyzing in vivo the impact of forced expression of ZAP-70 on the development and behavior of leukemias that arise in the Eμ-TCL1 transgenic (tg) mouse model of CLL. This model is characterized by the development of antigen-driven leukemias that resemble human CLL in many aspects but are always ZAP-70-negative. To force the expression of ZAP-70 in TCL1 leukemias, we generated two tg lines with targeted expression of ZAP-70 in the B cell compartment (ZAP70high and ZAP70low) and crossed them with Eμ-TCL1 tg mice. B cells in ZAP70high tg mice express similar levels of ZAP-70 as normal mouse T cells, whereas the levels of ZAP-70 in B cells of ZAP70lowtg mice are approximately 10 times lower. Both cohorts of Eμ-TCL1/ZAP70 double tg mice developed characteristic TCL1 leukemias. Eμ-TCL1/ZAP70low tg mice developed leukemias with onset and rate of progression similar to their ZAP-70-negative littermates, indicating that low levels of ZAP-70 do not alter the development and behavior of the disease. Surprisingly, Eμ-TCL1/ZAP70high tg mice developed leukemias with an approximately 2 month delay compared to their ZAP-70-negative Eμ-TCL1 tg littermates, which was contrary to the expectation that high ZAP-70 expression will accelerate leukemia development. The delay in leukemia development was especially evident at 6 months of age, when leukemic cells could be detected in the PB of 77% (10/13) of Eμ-TCL1 tg mice and only 24% (4/17) of Eμ-TCL1/ZAP70hightg mice (P=0.011). Since ZAP-70 expression can affect the migratory and adhesion capacity of human CLL cells in vitro, we first investigated if the delayed appearance of leukemic cells in the PB of Eμ-TCL1/ZAP70high tg mice could be due to increased retention of the leukemic cells in the lymphoid tissues. Assessment of tumor burden in the spleen, peritoneal cavity (PC), bone marrow and PB of 7 months old mice showed that the number of tumor cells in each compartment was significantly lower in Eμ-TCL1/ZAP70hightg mice than their Eμ-TCL1 littermates, suggesting that the delay in leukemia appearance is not caused by increased tissue retention but rather by reduced tumor growth. To investigate if ZAP-70 impairs tumor growth by affecting proliferation, we performed in vivo BrdU incorporation analysis of leukemic cells from spleen and PC of Eμ-TCL1 and Eμ-TCL1/ZAP70high tg mice. Spleen and PC samples were analyzed because they are the major sites of leukemia proliferation in Eμ-TCL1 tg mice. Interestingly, while the percentage of proliferating leukemic cells in the spleens of Eμ-TCL1 and Eμ-TCL1/ZAP70high tg mice was similar (mean % of BrdU+ cells ±SD: 6.81 ±1.67 and 6.15 ±2.92, respectively; P=n.s.), the percentage of proliferating leukemic cells in the PC of Eμ-TCL1/ZAP70high tg mice was significantly lower (mean % of BrdU+cells ±SD: 1.74 ±1.05 and 0.56 ±0.39, respectively; P=0.024). In summary, this study shows that ZAP-70 expression, per se, is unable to accelerate leukemia development and progression in an established in vivo model of CLL and suggests that ZAP-70 is not directly responsible for the greater disease severity in the poor prognosis subset of CLL. In addition, this study reveals that ZAP-70 in certain tissue environments can function as a negative regulator of leukemic cell proliferation, contrary to the widespread perception of ZAP-70 as a positive regulator of leukemic cell responses. Disclosures: No relevant conflicts of interest to declare.
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Gebbia, Vittorio, Pietro Citarrella, Vincenzo Miserendino, Roberto Valenza, Nicolò Borsellino, Antonio Pesta, Robert Pettit, and Stratford May. "The Effects of the Macrocyclic Lactone Bryostatin-1 on Leukemic Cells in Vitro." Tumori Journal 78, no. 3 (June 1992): 167–71. http://dx.doi.org/10.1177/030089169207800304.
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The macrocyclic lactone bryostatin-1 was found to exert in vitro antineoplastic activity against several leukemic cell lines, including human K562 erythroleukemia, HL60 promyelocytic leukemia, REH and MOLT-4 lymphoblastic leukemias, CCRFCEM lymphoma, KG-1 myeloid leukemia, and murine P388 lymphocytic leukemia. No statistically significant difference in sensitivity to bryostatin-1 was found between adriamycin-resistant P388 and K526 subclones and their sensitive counterparts. Freshly explanted clonogenic leukemic cells showed a variable sensitivity to bryostatin-1 in 10/12 tested samples. The IC50 of clonogenic leukemic cells was 4 × 10–3 M bryostatin-1, and that of normal marrow CFU-GM was 10–5 M. Leukemic cells exposed to bryostatin-1 showed a variable degree of monocytic differentiation as evaluated by ANAE staining and morphology. Bryostatin-1 is also able to inhibit the growth of CFU-GM from myelodysplastic marrow and to shorten the duration of dysplastic hematopoiesis in liquid culture. In conclusion, these data suggest that bryostatin-1 is a potent antileukemic agent in vitro that may be potentially useful for clinical studies.
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Jacob, Bindya, Motomi Osato, Namiko Yamashita, Chelsia Qiuxia Wang, Ichiro Taniuchi, Dan R. Littman, Norio Asou, and Yoshiaki Ito. "Stem cell exhaustion due to Runx1 deficiency is prevented by Evi5 activation in leukemogenesis." Blood 115, no. 8 (February 25, 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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Bento, Marta Leal, Luís Carvalho, Zhewei Chen, Ana Coelho, Cong Tang, and Gonçalo Bernardes. "Acute Myeloid and Lymphoblastic Leukemias: A NPM1 Targeting Strategy." Blood 142, Supplement 1 (November 28, 2023): 7147. http://dx.doi.org/10.1182/blood-2023-172497.
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Leukemia, a wide spectrum of diseases with altered proliferation and differentiation capacity of myeloid and lymphoid blood progenitors, is the most frequent type of cancer in children and one of the most common in adults. We discovered a covalent small-molecule “probe” for the treatment of acute myeloid and lymphoblastic leukemias that allows for post-translational modulation of the proteome in these leukemia cells. The probe dramatically induces apoptosis of leukemic cells at sub-toxic doses and consistently reduces proliferation, impairs cellular metabolism and promotes chemosensitization to “standard-of-care” chemotherapy regimens. Our proteomic analysis found specific targets that are critical to the leukemia cell survival, namely Nucleophosmin (NPM1) protein, which is a nucleolar phosphoprotein that performs diverse biological functions including molecular chaperoning, ribosome biogenesis, DNA repair, and genome stability. NPM1 gene mutations represent the most common genetic lesion in adult acute myeloid leukemia and their prognostic relevance earned them recognition as a distinct entity in the 2017 World Health Organization (WHO) classification of hematopoietic neoplasms. Our findings suggest a critical role of covalent inhibition of NPM1 in maintaining acute myeloid and lymphoblastic leukemia cells survival. This finding provides a rationale for therapeutic NPM1 modulation in acute leukemias.
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Swatler, Julian, Laura Turos-Korgul, Ewa Kozlowska, and Katarzyna Piwocka. "Immunosuppressive Cell Subsets and Factors in Myeloid Leukemias." Cancers 13, no. 6 (March 10, 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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Kumar, Bijender, Marvin Orellana, Jamison Brooks, Srideshikan Sargur Madabushi, Liliana E Parra, Darren Zuro, Qiong Wang, Ching-Cheng Chen, and Susanta Hui. "Leukemia Cells Remodel Adipocyte Niches and Their Progenitor Functions to Generate Leukemia Favoring Niche." Blood 132, Supplement 1 (November 29, 2018): 1294. http://dx.doi.org/10.1182/blood-2018-99-115689.
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Abstract Increasing evidence suggests that the cancer cells take shelter in different osteoblastic and adipocytic niches, where they hide from chemotherapy and continue to survive. As yet, how leukemia cells alter the bone marrow (BM) adipocytic niches to facilitate their expansion and assist them in evading chemotherapy is unclear. We have previously shown that the acute myeloid leukemia (AML) cells directly or through their exosomes, reprogram BM osteoblastic niche which facilitates their expansion and suppress normal hematopoiesis(Kumar B et al, Leukemia 2018,32(3):575-587). In this study , we provide further evidences that AML and Acute lymphoid leukemia (ALL) transformed the BM adipocytic niche to facilitate their expansion and suppress normal hematopoiesis. Using MLL-AF9 (AML) knock-in mouse, MLL-AF9 or BCR-ABL(p190, ALL) HSC transduction transplantation leukemia mice models, we performed flow cytometry analysis to show that the leukemia cells stimulate expansion of BM derived CD45-Ter119-CD31-CD166-Sca1+CD140a+(PaS)MSCs population compared to normal mice (p=0.04, p=0.001 and p=0.002 respectively).Further, the BM osteoblasts specific Osteocalcin mRNA expression in sorted stroma cells and flow cytometry based osteoblasts population (CD45-Ter119-CD31- CD166+Sca1-) numbers were also significantly reduced in AML (p=0.04) and ALL (p=0.02) mice models suggesting bone loss with the leukemia development. Similar to osteoblasts loss, mature adipocytes (Perilipin, PPARg mRNA) were also significantly reduced in the ALL/AML mice compared to control. The triglyceride content and white adipose tissue(WAT) mass was diminished in leukemic mice , suggesting leukemia may have utilized adipocyte for survival. Adipocyte loss in the leukemia mice was accompanied by long term hematopoietic stem cells(LT-HSC ) and erythroid megakaryocyte progenitor (MEP) populations reduction in the leukemic mice (p=0.01 and p=0.02 respectively). To dissect the mechanism of adipocytes reduction is either due to adipocyte loss or adipocytes maturation defect in leukemic mice, we analyzed different stromal progenitors in normal and leukemic mice and identified that the leukemia cells stimulate the growth of BM derived adipocytic committed progenitors (CD45-Ter119-CD31-CD166-Sca1+CD140a+CD29+CD24-) and blocked the chondrocyte/osteoblastic/adipocytic multipotent progenitors (CD45-Ter119-CD31- CD166-Sca1+CD140a+CD29+CD24+) population (p=0.02,p=0.01 respectively).Despite the increase in number of MSCs and adipocytic progenitors, the in-vitro adipocytic differentiation potential of sorted adipocyte committed progenitors was severely compromised in ALL and AML compared to control. The WAT western blot analysis showed significantly increased expression of ATGL and pHSL(Ser-563) expression involved in triglyceride lipolysis in the leukemic mice .The ALL leukemic adipocytic stroma had increased expression of IL-1β and IL-6 cytokine levels compared to normal stroma and provided more survival advantage to leukemia cells in in-vitro co-culture experiments in nutrient deprived conditions and during chemo-radiotherapy treatment. Further, the ATGL and HSL pharmacological inhibitors rescued leukemia induced lipolysis, reduced leukemia proliferation and increased chemotherapy induced apoptosis in leukemia cells. Overall, this data strongly suggests the notion of progressive decline in functional LT-HSCs & normal hematopoiesis, adipocytes and osteoblasts numbers with leukemia progression due to activation of lipolytic enzymes resulting in increased availability of fatty acids for leukemia expansion and is a common feature in both lymphoid and myeloid leukemias. Disclosures No relevant conflicts of interest to declare.
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Holden, JT, RB Geller, DC Farhi, HK Holland, LL Stempora, CN Phillips, and RA Bray. "Characterization of Thy-1 (CDw90) expression in CD34+ acute leukemia." Blood 86, no. 1 (July 1, 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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Jones, Letetia, Sabina Sevcikova, Vernon Phan, Sachi Jain, Angell Shieh, Joshua Dubansky, Min Li, et al. "Myc Drives Chromosomal Gain in Acute Myeloid Leukemia." Blood 112, no. 11 (November 16, 2008): 792. http://dx.doi.org/10.1182/blood.v112.11.792.792.
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Abstract Acute Myeloid Leukemia (AML) is a disease characterized by diverse genetic pathogenesis, including both balanced and unbalanced chromosomal aberrations. Much is known regarding the pathogenic effects of balanced rearrangements in AML, whereas our understanding of how unbalanced aberrations contribute to leukemia is more limited. The balanced t(15;17) chromosomal rearrangement is a nearly constant feature of acute promyeloctyic leukemia (APL), a subtype AML. The translocation fuses the promyelocytic leukemia gene (PML) to the retinoic acid receptor α gene (RARA). Trisomy 8 is the most common secondary karyotypic lesion observed in APL, and it has been speculated but not proven that the MYC gene contributes to this chromosomal gain. We previously reported that mouse chromosome 15, which contains the mouse Myc gene in a region syntenic to human chromosome 8q24, is commonly gained in the MRP8 PML-RARA mouse model of APL. We now report our work to assess the hypothesis that increased MYC cooperates with PML-RARα to accelerate disease and that gain of MYC/Myc drives +8 in humans and +15 in mice. Expressing MYC with a retroviral vector in PML-RARA bone marrow led to the rapid development of APL-like leukemias (3 months vs. 8.5 months with PML-RARA alone). Chromosome 15 was not gained in any of the leukemias, although 70% had other clonal karyotypic abnormalities. This finding suggests that when MYC is overexpressed, there is no selective pressure to gain chromosome 15, supporting our hypothesis that Myc is driving this gain. We also generated PML-RARA mice haploinsufficient for Myc to examine the effect of decreasing MYC levels. The median latency among leukemic animals was 258 days for mice with PML-RARA and two wild-type Myc alleles, whereas the latency was increased to 339 days for PML-RARA Myc haploinsufficient mice. Hence, lower MYC expression served as a check on leukemic transformation. Furthermore, the majority of the leukemias that arose in Myc haploinsufficient mice had gained wild-type Myc. These data demonstrate a selective pressure for Myc gain. Additional experiments showed that as MYC expression increases there is a decrease in both latency and genetic complexity of leukemias that arise, that MYC and PML-RARα interact to disrupt myeloid differentiation in vivo and that although MYC cooperates with PML-RARα to cause leukemia, additional events are required for completing transformation even at high levels of MYC. Altogether our studies of increased and decreased MYC expression in PML-RARA mice show a strong correlation between MYC dosage and leukemic transformation. Our results suggest that agents that target MYC might be useful for the treatment of AML.
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Segawa, Hidekazu, Shinya Kimura, Junya Kuroda, Takeshi Yuasa, and Taira Maekawa. "Zoledronate Inhibits Leukemia Growth in Bone Marrow and Synergizes with Imatinib Mesylate Against Ph+ Primary Leukemic Cells." Blood 104, no. 11 (November 16, 2004): 2096. http://dx.doi.org/10.1182/blood.v104.11.2096.2096.
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Abstract Imatinib mesylate has drastically changed Philadelphia chromosome positive (Ph+) leukemia treatment. However, remissions induced in advanced phase Ph+ leukemias tend to be short-lived even treated with imatinib. Combined therapy of imatinib with an agent which inhibits downstream signaling of BCR/ABL such as Ras is intriguing. Phase I studies of farnesyl transferase inhibitors (FTIs), which targeted farnesylation of Ras, with imatinib against Ph+ leukemias demonstrated limited combination effects. We previously reported that the third-generation bisphosphonates (BPs) zoledronate (ZOL) synergized with imatinib mesylate to inhibit Ph+ leukemia. BPs which inhibit both farnesylation and geranylgeranylation of Ras proteins may be more potent than FTIs. However, three important questions have remained unanswered to promote this attractive combination to a clinical trial. Concentrations of 20-30 μM ZOL are required in vitro to induce apoptosis in leukemic cell lines. However, peak serum concentrations after infusion of 4 mg ZOL were 1–2 μM. Therefore, it is important to investigate how ZOL achieves effective concentrations in vivo. The second is whether ZOL augments the effects of imatinib against not only cell lines but also primary cells from Ph+ leukemia patients. In addition, the safety of this combination therapy must be established, because the dose of ZOL used in our previous study was high compared with clinical doses administered for inhibition of bone lesions. To answer these questions, we herein investigated about the combination therapy of ZOL plus imatinib using NOD/SCID mice engrafted with primary Ph+ leukemic cells with or without mutations in the ATP binding site. ZOL inhibited the geranylgeranylation of Ras proteins of leukemic cells in bone marrow but not in peripheral blood, indicating that sufficient concentration of ZOL could be achieved in bone marrow. ZOL synergized with imatinib to enhance survival of mice engrafted with primary Ph+ leukemic cells without mutations and this combination was well-tolerated without any severe adverse effects. These findings suggest that ZOL inhibits leukemia growth in bone marrow and the combination of ZOL plus imatinib is a potential therapy for Ph+ leukemia patients.
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Dinndorf, PA, RG Andrews, D. Benjamin, D. Ridgway, L. Wolff, and ID Bernstein. "Expression of normal myeloid-associated antigens by acute leukemia cells." Blood 67, no. 4 (April 1, 1986): 1048–53. http://dx.doi.org/10.1182/blood.v67.4.1048.1048.
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Abstract Monoclonal antibodies that react with hematopoietic cells and their precursors in a stage and lineage restricted fashion were used in indirect immunofluorescence assays to examine leukemic cells from 105 pediatric age patients. The differentiative states of blasts from 42 patients with acute nonlymphocytic leukemia (ANLL) were defined by these antibodies. When these were compared to their morphologic and histochemical levels of differentiation as defined by the French- American-British (FAB) classification, no direct relationship was found. The reactivity of these antibodies with leukemic cells from 63 patients with acute lymphocytic leukemiA (ALL) was also investigated, and the usefulness of these antibodies in distinguishing leukemias of myeloid from those of lymphoid origin was demonstrated.
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Dinndorf, PA, RG Andrews, D. Benjamin, D. Ridgway, L. Wolff, and ID Bernstein. "Expression of normal myeloid-associated antigens by acute leukemia cells." Blood 67, no. 4 (April 1, 1986): 1048–53. http://dx.doi.org/10.1182/blood.v67.4.1048.bloodjournal6741048.
Full textAbstract:
Monoclonal antibodies that react with hematopoietic cells and their precursors in a stage and lineage restricted fashion were used in indirect immunofluorescence assays to examine leukemic cells from 105 pediatric age patients. The differentiative states of blasts from 42 patients with acute nonlymphocytic leukemia (ANLL) were defined by these antibodies. When these were compared to their morphologic and histochemical levels of differentiation as defined by the French- American-British (FAB) classification, no direct relationship was found. The reactivity of these antibodies with leukemic cells from 63 patients with acute lymphocytic leukemiA (ALL) was also investigated, and the usefulness of these antibodies in distinguishing leukemias of myeloid from those of lymphoid origin was demonstrated.
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Horton, Sarah J., Vanessa Walf-Vorderwülbecke, Steve J. Chatters, Neil J. Sebire, Jasper de Boer, and Owen Williams. "Acute Myeloid Leukemia Induced by MLL-ENL Is Cured by Oncogene Ablation despite Acquisition of Complex Genetic Abnormalities." Blood 112, no. 11 (November 16, 2008): 3109. http://dx.doi.org/10.1182/blood.v112.11.3109.3109.
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Abstract Chromosomal translocations involving the Mixed-Lineage-Leukemia (MLL) gene on chromosome 11q23 are frequent in infant acute leukemia and give rise to the formation of MLL-fusion genes. Several studies have addressed the importance of MLL-fusion activity for the initiation and maintenance of hematopoietic transformation. However, the dependence of established leukemias on MLL-fusion activity has not been previously addressed. 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. In this study, immortalized myeloid cells conditionally or constitutively expressing the MLL-ENL fusion gene were used to induce acute myeloid leukemia (AML) in vivo. Primary recipients developed AML with a mean latency of 81.4 (±4.8) days. Secondary recipients developed AML with much shorter latencies than primary recipients regardless of whether the leukemic cells were freshly transplanted (26.8 (±6.8) days) or cultured in vitro for one month prior to transplantation (18 (±3.9) days). Genetic analysis revealed that some leukemic cells had acquired gross chromosomal abnormalities such as trisomy 6 or gains and losses of chromosome regions, which were not detected in the immortalised cells from which they were derived. Despite the acquisition of additional genetic abnormalities, the leukemic cells remained dependent upon MLL-ENL expression in vitro and in vivo. The leukemic cells terminally differentiated into neutrophils upon doxycycline treatment in vitro and established leukemias regressed following administration of doxycycline to recipient mice in their drinking water. Leukemic regression was accompanied by the complete loss of leukemic cells from the peripheral blood and differentiation of leukemic cells in the spleen. In 7 out of 34 doxycycline treated mice, remission was not sustained and the leukemias relapsed. However, most of these were shown to have acquired constitutive expression of MLL-ENL. This study demonstrates that leukemic cells are addicted to MLL-ENL expression and suggests that targeting the transcriptional/signalling networks established by MLL-fusion oncogenes in patients with 11q23 rearrangements would be a major therapeutic advance.
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Caudell, David, David P. Harper, Rachel L. Novak, Rachel M. Pierce, Christopher Slape, Linda Wolff, and Peter D. Aplan. "Retroviral insertional mutagenesis identifies Zeb2 activation as a novel leukemogenic collaborating event in CALM-AF10 transgenic mice." Blood 115, no. 6 (February 11, 2010): 1194–203. http://dx.doi.org/10.1182/blood-2009-04-216184.
Full textAbstract:
AbstractThe t(10;11) translocation results in a CALM-AF10 fusion gene in a subset of leukemia patients. Expression of a CALM-AF10 transgene results in leukemia, with prolonged latency and incomplete penetrance, suggesting that additional events are necessary for leukemic transformation. CALM-AF10 mice infected with the MOL4070LTR retrovirus developed acute leukemia, and ligation-mediated polymerase chain reaction was used to identify retroviral insertions at 19 common insertion sites, including Zeb2, Nf1, Mn1, Evi1, Ift57, Mpl, Plag1, Kras, Erg, Vav1, and Gata1. A total of 26% (11 of 42) of the mice had retroviral integrations near Zeb2, a transcriptional corepressor leading to overexpression of the Zeb2-transcript. A total of 91% (10 of 11) of mice with Zeb2 insertions developed B-lineage acute lymphoblastic leukemia, suggesting that Zeb2 activation promotes the transformation of CALM-AF10 hematopoietic precursors toward B-lineage leukemias. More than half of the mice with Zeb2 integrations also had Nf1 integrations, suggesting cooperativity among CALM-AF10, Zeb2, and Ras pathway mutations. We searched for Nras, Kras, and Ptpn11 point mutations in the CALM-AF10 leukemic mice. Three mutations were identified, all of which occurred in mice with Zeb2 integrations, consistent with the hypothesis that Zeb2 and Ras pathway activation promotes B-lineage leukemic transformation in concert with CALM-AF10.
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Dutta, Sayantanee, Alexandre Krause, Sebastian Vosberg, Tobias Herold, Bianca Ksienzyk, Leticia Quintanilla-Fend, Belay Tizazu, et al. "Analysis of the Tissue-Specific Expression Requirements and Identification of Cooperating Mutations for Leukemogenesis in an Inducible CALM/AF10 Knock-in Mouse Model." Blood 124, no. 21 (December 6, 2014): 126. http://dx.doi.org/10.1182/blood.v124.21.126.126.
Full textAbstract:
Abstract The CALM/AF10 fusion, which is the result of the t(10;11)(p12;q14), is associated with various hematological malignancies including acute myeloid leukemia (AML), T cell acute lymphoblastic leukemia (ALL) and malignant lymphoma, and has usually a poor prognosis. We established a CALM/AF10 knock-in mouse model, which allows tissue-specific expression of the fusion gene. The CALM/AF10 fusion gene, preceded by a loxP site flanked transcriptional stop cassette, was knocked into the Rosa26 locus (R26LSLCA strain). Tissue-specific CALM/AF10 expression was achieved by crossing R26LSLCA mice with three Cre inducer lines expressing the Cre recombinase under the control of defined promoters (Vav-Cre, Mb1-Cre, CD19-Cre). Acute leukemia developed in all (n=23) Vav-Cre/R26LSLCA mice with a median latency of 12 months. In the Vav-Cre line, the Cre recombinase is expressed in all hematopoietic cells including stem cells. Leukemias were either myeloid or had a combination of myeloid and lymphoid features with the expression of the B cell marker B220. The leukemia in these mice was characterized by leukocytosis, splenomegaly and bone marrow as well as multi organ infiltration of myeloid blast like cells. In contrast, none of the mice with the Mb1-Cre/R26LSLCA (n=25) or the CD19-Cre/R26LSLCA (n=20) genotype, which expressed the CALM/AF10 from the early B cell progenitor stage, developed leukemia, even though the B cells of these mice expressed the CALM/AF10 transcript at comparable levels to the levels observed in the bone marrow and spleen cells of the leukemic mice. Affymetrix gene expression profiling (GEP) of leukemic and pre-leukemic bone marrow cells of Vav-Cre/R26LSLCA mice revealed that high expression of Hoxa cluster genes and the Hox co-factor Meis1 occurred before the onset of overt leukemia. The B cells from Mb1-Cre/R26LSLCA mice did not show higher expression of Hoxa cluster genes or of Meis1 compared to B cells from wild type mice. The long latency to leukemia development in the Vav-Cre/R26LSLCA mice suggested that additional genetic lesions were required to cooperate with the CALM/AF10 fusion to lead to malignant transformation. To identify these lesion, we performed whole exome sequencing (WES) on the DNA from the leukemic cells of 8 Vav-Cre/R26LSLCA mice and compared the sequence to the corresponding germ line DNA and a pool of 10 germline control WES datasets. We identified between 1 and 6 somatic point mutations and indels per sample in the 5 exomes with the highest product of percent exome coverage at more than 10x and blast percentage (10x coverage: range 22 to 91%, median 86%). There was a median of 4 somatic nonsense and missense mutations per exome in the 5 exomes, with a strong tendency for more mutations being identified in the exomes with higher coverage and higher blast percentages. Even though only a small number of leukemias was analyzed by WES, two leukemia exomes had recurring mutations in the same gene (4930595M18Rik), and two other leukemias had mutations in known leukemia drivers involved in cellular proliferation pathways. One leukemia carried an activating mutation in the tyrosine kinase domain of Flt3, and in another exome a mutation in the catalytic domain of the intracellular protein tyrosine phosphatase Ptpn11 was found. PTPN11 is a downstream effector of the Ras pathway and mutations in PTPN11 is repoted in juvenile myelomonocytic leukemia (JMML) and Noonan sydnrome. There was no obvious correlation between the mutations and the type of leukemia (myeloid or myeloid with B220 expression) observed in the mice. Our results strongly suggest that leukemia only develops if CALM/AF10 is expressed in hemaptoietic stem cells. Expression of CALM/AF10 in B cells is not sufficient for transformation. Presumably, the expression of CALM/AF10 in long-lived hematopoietic stem cells allows for the acquisition of additional, cooperating mutations, which are required for full leukemic transformation.The reproducibility and relatively long latency of leukemia development in the Vav-Cre/R26LSLCA mice should make them a good model for the study of clonal evolution and collaborating events in leukemogenesis. Disclosures No relevant conflicts of interest to declare.
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Aue, Georg, Yang Du, Susan M. Cleveland, Stephen B. Smith, Utpal P. Davé, Delong Liu, Marc A. Weniger, et al. "Sox4 cooperates with PU.1 haploinsufficiency in murine myeloid leukemia." Blood 118, no. 17 (October 27, 2011): 4674–81. http://dx.doi.org/10.1182/blood-2011-04-351528.
Full textAbstract:
Abstract Cooperation of multiple mutations is thought to be required for cancer development. In previous studies, murine myeloid leukemias induced by transducing wild-type bone marrow progenitors with a SRY sex determining region Y-box 4 (Sox4)–expressing retrovirus frequently carried proviral insertions at Sfpi1, decreasing its mRNA levels, suggesting that reduced Sfpi1 expression cooperates with Sox4 in myeloid leukemia induction. In support of this hypothesis, we show here that mice receiving Sox4 virus-infected Sfpi1ko/+ bone marrow progenitors developed myeloid leukemia with increased penetrance and shortened latency. Interestingly, Sox4 expression further decreased Sfpi1 transcription. Ectopic SOX4 expression reduced endogenous PU.1 mRNA levels in HL60 promyelocytes, and decreased Sfpi1 mRNA levels were also observed in the spleens of leukemic and preleukemic mice receiving Sox4 virus-infected wild-type bone marrow cells. In addition, Sox4 protein bound to a critical upstream regulatory element of Sfpi1 in ChIP assays. Such cooperation probably occurs in de novo human acute myeloid leukemias, as an analysis of 285 acute myeloid leukemia patient samples found a significant negative correlation between SOX4 and PU.1 expression. Our results establish a novel cooperation between Sox4 and reduced Sfpi1 expression in myeloid leukemia development and suggest that SOX4 could be an important new therapeutic target in human acute myeloid leukemia.