A Gain-of-Function p53-Mutant Oncogene Promotes Cell Fate Plasticity and Myeloid Leukemia through the Pluripotency Factor FOXH1.
Cancer Discov
; 9(7): 962-979, 2019 07.
Article
en En
| MEDLINE
| ID: mdl-31068365
ABSTRACT
Mutations in the TP53 tumor suppressor gene are common in many cancer types, including the acute myeloid leukemia (AML) subtype known as complex karyotype AML (CK-AML). Here, we identify a gain-of-function (GOF) Trp53 mutation that accelerates CK-AML initiation beyond p53 loss and, surprisingly, is required for disease maintenance. The Trp53R172H mutation (TP53R175H in humans) exhibits a neomorphic function by promoting aberrant self-renewal in leukemic cells, a phenotype that is present in hematopoietic stem and progenitor cells (HSPC) even prior to their transformation. We identify FOXH1 as a critical mediator of mutant p53 function that binds to and regulates stem cell-associated genes and transcriptional programs. Our results identify a context where mutant p53 acts as a bona fide oncogene that contributes to the pathogenesis of CK-AML and suggests a common biological theme for TP53 GOF in cancer. SIGNIFICANCE:
Our study demonstrates how a GOF p53 mutant can hijack an embryonic transcription factor to promote aberrant self-renewal. In this context, mutant Trp53 functions as an oncogene to both initiate and sustain myeloid leukemia and suggests a potential convergent activity of mutant Trp53 across cancer types.This article is highlighted in the In This Issue feature, p. 813.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Células Madre Neoplásicas
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Leucemia Mieloide Aguda
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Proteína p53 Supresora de Tumor
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Factores de Transcripción Forkhead
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Mutación con Ganancia de Función
Tipo de estudio:
Prognostic_studies
Límite:
Animals
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Humans
Idioma:
En
Revista:
Cancer Discov
Año:
2019
Tipo del documento:
Article