p53-/- synergizes with enhanced NrasG12D signaling to transform megakaryocyte-erythroid progenitors in acute myeloid leukemia.
Blood
; 129(3): 358-370, 2017 01 19.
Article
en En
| MEDLINE
| ID: mdl-27815262
ABSTRACT
Somatic mutations in TP53 and NRAS are associated with transformation of human chronic myeloid diseases to acute myeloid leukemia (AML). Here, we report that concurrent RAS pathway and TP53 mutations are identified in a subset of AML patients and confer an inferior overall survival. To further investigate the genetic interaction between p53 loss and endogenous NrasG12D/+ in AML, we generated conditional NrasG12D/+p53-/- mice. Consistent with the clinical data, recipient mice transplanted with NrasG12D/+p53-/- bone marrow cells rapidly develop a highly penetrant AML. We find that p53-/- cooperates with NrasG12D/+ to promote increased quiescence in megakaryocyte-erythroid progenitors (MEPs). NrasG12D/+p53-/- MEPs are transformed to self-renewing AML-initiating cells and are capable of inducing AML in serially transplanted recipients. RNA sequencing analysis revealed that transformed MEPs gain a partial hematopoietic stem cell signature and largely retain an MEP signature. Their distinct transcriptomes suggests a potential regulation by p53 loss. In addition, we show that during AML development, transformed MEPs acquire overexpression of oncogenic Nras, leading to hyperactivation of ERK1/2 signaling. Our results demonstrate that p53-/- synergizes with enhanced oncogenic Nras signaling to transform MEPs and drive AML development. This model may serve as a platform to test candidate therapeutics in this aggressive subset of AML.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Leucemia Mieloide Aguda
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Transformación Celular Neoplásica
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Proteína p53 Supresora de Tumor
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Células Progenitoras de Megacariocitos y Eritrocitos
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GTP Fosfohidrolasas
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Proteínas de la Membrana
Tipo de estudio:
Etiology_studies
Límite:
Animals
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Humans
Idioma:
En
Revista:
Blood
Año:
2017
Tipo del documento:
Article