학술논문
Germline duplication of ATG2B and GSKIP predisposes to familial myeloid malignancies.
Document Type
Article
Author
Saliba, Joseph; Saint-Martin, Cécile; Di Stefano, Antonio; Lenglet, Gaëlle; Marty, Caroline; Pasquier, Florence; Valle, Véronique Della; Secardin, Lise; Mahfoudhi, Emna; Grosjean, Sarah; Droin, Nathalie; Diop, M'boyba; Dessen, Philippe; Palazzo, Alberta; Merlevede, Jane; Isnard, Françoise; Casadevall, Nicole; Solary, Eric; Debili, Najet; Bernard, Olivier A
Source
Subject
*MYELODYSPLASTIC syndromes
*GERM cells
*TUMORS
*LEUKEMIA risk factors
*THROMBOPOIETIN
*THROMBOCYTOPENIA
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Language
ISSN
1061-4036
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 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. [ABSTRACT FROM AUTHOR]