Somatic mutations associated with leukemic progression of familial platelet disorder with predisposition to acute myeloid leukemia

The familial platelet disorder with predisposition to acute myeloid leukemia (FPD/AML) represents a unique model to study leukemic progression. Whereas qualitative or quantitative platelet defects are a constant feature of the disease, the onset of the hematological malignancy can be very heterogene...

Descripción completa

Detalles Bibliográficos
Autores: Antony Debré, I., Duployez, N., Bucci, M., Geffroy, S., Micol, J.-B., Renneville, A., Boissel, N., Dhédin, N., Réa, D., Nelken, B., Berthon, C., Leblanc, T., Mozziconacci, M. J., Favier, R., Heller, Paula Graciela, Abdel Wahab, O., Raslova, H., Latger Cannard, V., Preudhomme, C.
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2016
País:Argentina
Institución:Consejo Nacional de Investigaciones Científicas y Técnicas
Repositorio:CONICET Digital (CONICET)
Idioma:inglés
OAI Identifier:oai:ri.conicet.gov.ar:11336/39326
Acceso en línea:http://hdl.handle.net/11336/39326
Access Level:acceso abierto
Palabra clave:Runx1
Leukemia
Platelet
https://purl.org/becyt/ford/3.2
https://purl.org/becyt/ford/3
Descripción
Sumario:The familial platelet disorder with predisposition to acute myeloid leukemia (FPD/AML) represents a unique model to study leukemic progression. Whereas qualitative or quantitative platelet defects are a constant feature of the disease, the onset of the hematological malignancy can be very heterogeneous and the molecular mechanisms responsible for leukemia progression remain poorly understood. We analyzed a cohort of 25 individuals from 15 FPD/AML pedigrees for mutations in 44 AML-associated genes, including genes recently associated with germline or acquired RUNX1 aberrations such as CDC25C, GATA2 and ASXL1/2. Of the 25 patients, 13 were studied following acute leukemia development (10 with acute myeloid leukemia (AML) and 3 with T-cell acute lymphoblastic leukemia). Interestingly, a second, somatically acquired alteration in RUNX1 was found in nearly all patients who developed AML, including second mutation, copy neutral loss of heterozygosity or duplication of the RUNX1-mutated or -deleted allele. These latter two events were identified by analysis of the allelic ratio coupled with karyotype. Additional somatic mutations in genes implicated in signaling, RNA splicing or epigenetic regulation were also identified at leukemic transformation. Our findings suggest that biallelic RUNX1 alterations are crucial for AML development in FPD/AML.

Similares en LA Referencia