Chronic myelogenous leukemia in blast crisis

Kantarjian, Hagop M.; Keating, Michael J.; Talpaz, Moshe; Walters, Ronald S.; Smith, Terry L.; Cork, Ann; McCredie, Kenneth B.; Freireich, Emil J.

doi:10.1016/0002-9343(87)90754-6

Cited by 271 publications

(175 citation statements)

References 31 publications

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“…23 Most authors have shown that the finding of additional changes is associated with reduced survival, but this is not universally agreed. [24][25][26][27][28][29] In this study approximately 65% of patients had additional cytogenetic changes and evidence of cytogenetic evolution was an independent adverse prognostic factor for survival. Its presence, however, had no impact on response to first therapy.…”

Section: Discussionmentioning

confidence: 56%

Factors affecting duration of survival after onset of blastic transformation of chronic myeloid leukemia

Wadhwa

Szydlo

Apperley

et al. 2002

Blood

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Section: Discussionmentioning

confidence: 56%

Factors affecting duration of survival after onset of blastic transformation of chronic myeloid leukemia

Wadhwa

Szydlo

Apperley

et al. 2002

Blood

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“…p53-inactivating mutations were identified in o15% of chronic phase hematological malignancies, including chronic myelogenous leukemia (Kantarjian et al, 1987;Feinstein et al, 1991;Hernandez-Boussard et al, 1999), PV (Gaidano et al, 1997) and PMF (Tsurumi et al, 2002;Reilly, 2005) and more than half of MPN in blast crisis (Gaidano et al, 1997;Tsurumi et al, 2002). In the absence of mutation, p53 function can be inactivated by an increased expression of MDM2, an E3 ubiquitin ligase that binds to p53 and promotes its proteosomal degradation (Freedman et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

JAK2V617F negatively regulates p53 stabilization by enhancing MDM2 via La expression in myeloproliferative neoplasms

et al. 2011

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JAK2 V617F is a gain of function mutation that promotes cytokine-independent growth of myeloid cells and accounts for a majority of myeloproliferative neoplasms (MPN). Mutations in p53 are rarely found in these diseases before acute leukemia transformation, but this does not rule out a role for p53 deregulation in disease progression. Using Ba/ F3-EPOR cells and ex vivo cultured CD34 þ cells from MPN patients, we demonstrate that expression of JAK2 V617F affected the p53 response to DNA damage. We show that E3 ubiquitin ligase MDM2 accumulated in these cells, due to an increased translation of MDM2 mRNA. Accumulation of the La autoantigen, which interacts with MDM2 mRNA and promotes its translation, was responsible for the increase in MDM2 protein level and the subsequent degradation of p53 after DNA damage. Downregulation of La protein or cell treatment with nutlin-3, a MDM2 antagonist, restored the p53 response to DNA damage and the cytokine-dependence of Ba/F3-EPOR-JAK2 V617F cells. Altogether, these data indicate that the JAK2 V617F mutation affects p53 response to DNA damage through the upregulation of La antigen and accumulation of MDM2. They also suggest that p53 functional inactivation accounts for the cytokine hypersensitivity of JAK2 V617F MPN and might have a role in disease progression.

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“…1,2 Chemotherapy-resistant blasts are a frequent cause of treatment failure in these patients. 3 In many cases, the blasts exhibit a multi-drug resistance phenotype.…”

Section: Introductionmentioning

confidence: 99%

Diphtheria toxin fused to human interleukin-3 is toxic to blasts from patients with myeloid leukemias

et al. 2000

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Leukemic blasts from patients with acute phase chronic myeloid leukemic and refractory acute myeloid leukemia are highly resistant to a number of cytotoxic drugs. To overcome multi-drug resistance, we engineered a diphtheria fusion protein by fusing human interleukin-3 (IL3) to a truncated form of diphtheria toxin (DT) with a (G 4 S) 2 linker (L), expressed and purified the recombinant protein, and tested the cytotoxicity of the DTLIL3 molecule on human leukemias and normal progenitors. The DTLIL3 construct was more cytotoxic to interleukin-3 receptor (IL3R) bearing human myeloid leukemia cell lines than receptor-negative cell lines based on assays of cytotoxicity using thymidine incorporation, growth in semi-solid medium and induction of apoptosis. Exposure of mononuclear cells to 680 pM DTLIL3 for 48 h in culture reduced the number of cells capable of forming colonies in semi-solid medium (colony-forming units leukemia) у10-fold in 4/11 (36%) patients with myeloid acute phase chronic myeloid leukemia (CML) and 3/9 (33%) patients with acute myeloid leukemia (AML). Normal myeloid progenitors (colony-forming unit granulocytemacrophage) from five different donors treated and assayed under identical conditions showed intermediate sensitivity with three-to five-fold reductions in colonies. The sensitivity to DTLIL3 of leukemic progenitors from a number of acute phase CML patients suggests that this agent could have therapeutic potential for some patients with this disease. Leukemia (2000) 14, 576-585.

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Chronic myelogenous leukemia in blast crisis

Cited by 271 publications

References 31 publications

Factors affecting duration of survival after onset of blastic transformation of chronic myeloid leukemia

Factors affecting duration of survival after onset of blastic transformation of chronic myeloid leukemia

JAK2V617F negatively regulates p53 stabilization by enhancing MDM2 via La expression in myeloproliferative neoplasms

Diphtheria toxin fused to human interleukin-3 is toxic to blasts from patients with myeloid leukemias

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