학술논문
Germline duplication of ATG2B and GSKIP predisposes to familial myeloid malignancies
Document Type
Report
Author
Saliba, Joseph; Saint-Martin, Cecile; Di Stefano, Antonio; Lenglet, Gaelle; Marty, Caroline; Keren, Boris; Pasquier, Florence; Valle, Veronique Della; Secardin, Lise; Leroy, Gwendoline; Mahfoudhi, Emna; Grosjean, Sarah; Droin, Nathalie; Diop, M'boyba; Dessen, Philippe; Charrier, Sabine; Palazzo, Alberta; Merlevede, Jane; Meniane, Jean-Come; Delaunay-Darivon, Christine; Fuseau, Pascal; Isnard, Francoise; Casadevall, Nicole; Solary, Eric; Debili, Najet; Bernard, Olivier A.; Raslova, Hana; Najman, Albert; Vainchenker, William; Bellanne-Chantelot, Christine; Plo, Isabelle
Source
Nature Genetics. October 1, 2015, p1131, 12 p.
Subject
Language
English
ISSN
1061-4036
Abstract
Most myeloid malignancies, including acute myeloid leukemias (AML), myelodysplastic syndromes (MOS) and MPN, are sporadic diseases. Familial forms are rare but informative, as germline mutations may phenocopy initiating mutations in [...]
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.
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.