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.
journal_name
Nat Genetjournal_title
Nature geneticsauthors
Saliba J,Saint-Martin C,Di Stefano A,Lenglet G,Marty C,Keren B,Pasquier F,Valle VD,Secardin L,Leroy G,Mahfoudhi E,Grosjean S,Droin N,Diop M,Dessen P,Charrier S,Palazzo A,Merlevede J,Meniane JC,Delaunay-Darivon C,Fdoi
10.1038/ng.3380subject
Has Abstractpub_date
2015-10-01 00:00:00pages
1131-40issue
10eissn
1061-4036issn
1546-1718pii
ng.3380journal_volume
47pub_type
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