RESUMO
To better understand the origin of leukemic stem cells, we tested the hypothesis that all leukemia oncogenes could transform committed myeloid progenitor cells lacking the capacity for self-renewal, as has recently been reported for MLL-ENL. Flow-sorted populations of common myeloid progenitors and granulocyte-monocyte progenitors were transduced with the oncogenes MOZ-TIF2 and BCR-ABL, respectively. MOZ-TIF2-transduced progenitors could be serially replated in methylcellulose cultures and continuously propagated in liquid culture, and resulted in an acute myeloid leukemia in vivo that could be serially transplanted. In contrast, BCR-ABL transduction conferred none of these properties to hematopoietic progenitors. These data demonstrate that some, but not all, leukemia oncogenes can confer properties of leukemic stem cells to hematopoietic progenitors destined to undergo apoptotic cell death.
Assuntos
Transformação Celular Neoplásica/genética , Genes abl/fisiologia , Células-Tronco Hematopoéticas/patologia , Proteínas de Fusão Oncogênica/fisiologia , Doença Aguda , Animais , Southern Blotting , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Diferenciação Celular/genética , Linhagem da Célula , Proliferação de Células/efeitos dos fármacos , Transformação Celular Neoplásica/patologia , Ensaio de Unidades Formadoras de Colônias , Citometria de Fluxo , Genes abl/genética , Células Precursoras de Granulócitos/metabolismo , Células Precursoras de Granulócitos/patologia , Células-Tronco Hematopoéticas/metabolismo , Humanos , Imunofenotipagem , Interleucina-3/farmacologia , Leucemia Mieloide/genética , Leucemia Mieloide/patologia , Camundongos , Camundongos Endogâmicos C57BL , Modelos Biológicos , Mutação , Células Progenitoras Mieloides/metabolismo , Células Progenitoras Mieloides/patologia , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Proteínas de Fusão Oncogênica/genéticaRESUMO
FIP1L1-PDGFRalpha causes hypereosinophilic syndrome (HES) and is inhibited by the tyrosine kinase inhibitor imatinib (Gleevec). Imatinib is a potent inhibitor of ABL, ARG, PDGFRalpha, PDGFRbeta, and KIT and induces durable hematologic responses in HES patients. However, we observed relapse with resistance to imatinib as consequence of a T674I mutation in FIP1L1-PDGFRalpha, analogous to the imatinib-resistant T315I mutation in BCR-ABL. We developed a murine bone marrow transplant model of FIP1L1-PDGFRalpha-induced myeloproliferative disease to evaluate the efficacy of PKC412, an alternative inhibitor of PDGFRalpha, for the treatment of HES. PKC412 is effective for treatment of FIP1L1-PDGFRalpha-induced disease and of imatinib-induced resistance due to the T674I mutation. Our data establish PKC412 as molecularly targeted therapy for HES and other diseases expressing activated PDGFRalpha and demonstrate the potential of alternative kinase inhibitors to overcome resistance in target tyrosine kinases.
Assuntos
Transtornos Mieloproliferativos/tratamento farmacológico , Piperazinas/uso terapêutico , Pirimidinas/uso terapêutico , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Estaurosporina/análogos & derivados , Estaurosporina/uso terapêutico , Fatores de Poliadenilação e Clivagem de mRNA/metabolismo , Animais , Antineoplásicos/farmacologia , Benzamidas , Western Blotting , Medula Óssea/patologia , Transplante de Medula Óssea , Linhagem Celular , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Resistência a Medicamentos , Proteínas de Fusão bcr-abl/metabolismo , Vetores Genéticos , Humanos , Mesilato de Imatinib , Imunofenotipagem , Camundongos , Modelos Genéticos , Mutação , Testes de Precipitina , Recidiva , Retroviridae/genética , Baço/citologia , Fatores de TempoRESUMO
Homozygous loss of function of Runx1 (Runt-related transcription factor 1 gene) during murine development results in an embryonic lethal phenotype characterized by a complete lack of definitive hematopoiesis. In light of recent reports of disparate requirements for hematopoietic transcription factors during development as opposed to adult hematopoiesis, we used a conditional gene-targeting strategy to effect the loss of Runx1 function in adult mice. In contrast with the critical role of Runx1 during development, Runx1 was not essential for hematopoiesis in the adult hematopoietic compartment, though a number of significant hematopoietic abnormalities were observed. Runx1 excision had lineage-specific effects on B- and T-cell maturation and pronounced inhibition of common lymphocyte progenitor production. Runx1 excision also resulted in inefficient platelet production. Of note, Runx1-deficient mice developed a mild myeloproliferative phenotype characterized by an increase in peripheral blood neutrophils, an increase in myeloid progenitor populations, and extramedullary hematopoiesis composed of maturing myeloid and erythroid elements. These findings indicate that Runx1 deficiency has markedly different consequences during development compared with adult hematopoiesis, and they provide insight into the phenotypic manifestations of Runx1 deficiency in hematopoietic malignancies.