Germline duplication of ATG2B and GSKIP predisposes to familial myeloid malignancies
CHARRIER, S.
Approches génétiques intégrées et nouvelles thérapies pour les maladies rares [INTEGRARE]
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Approches génétiques intégrées et nouvelles thérapies pour les maladies rares [INTEGRARE]
Language
en
Article de revue
This item was published in
Nat Genet. 2015-10, vol. 47, n° 10, p. 1131-40
English Abstract
No major predisposition gene for familial myeloproliferative neoplasms (MPN) has been identified. Here we demonstrate that the autosomal dominant transmission of a 700-kb duplication in four genetically related families ...Read more >
No major predisposition gene for familial myeloproliferative neoplasms (MPN) has been identified. Here we demonstrate that the autosomal dominant transmission of a 700-kb duplication in four genetically related families predisposes to myeloid malignancies, including MPN, frequently progressing to leukemia. Using induced pluripotent stem cells and primary cells, we demonstrate that overexpression of ATG2B and GSKIP enhances hematopoietic progenitor differentiation, including of megakaryocytes, by increasing progenitor sensitivity to thrombopoietin (TPO). ATG2B and GSKIP cooperate with acquired JAK2, MPL and CALR mutations during MPN development. Thus, the germline duplication may change the fitness of cells harboring signaling pathway mutations and increases the probability of disease development.Read less <
Origin
Hal imported