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. 2015 Oct;47(10):1131-40.
doi: 10.1038/ng.3380. Epub 2015 Aug 17.

Germline duplication of ATG2B and GSKIP predisposes to familial myeloid malignancies

Joseph Saliba  1   2   3   4 , Cécile Saint-Martin  1   2   3   5 , Antonio Di Stefano  1   2   3   4 , Gaëlle Lenglet  1   2   3   4 , Caroline Marty  1   2   3   4 , Boris Keren  5 , Florence Pasquier  1   2   3   4 , Véronique Della Valle  1   2   3 , Lise Secardin  1   2   3   4 , Gwendoline Leroy  5 , Emna Mahfoudhi  1   2   3   4   6 , Sarah Grosjean  1   2   3   4 , Nathalie Droin  1   2   3 , M'boyba Diop  1   2   3 , Philippe Dessen  1   2   3 , Sabine Charrier  7 , Alberta Palazzo  1   2   3 , Jane Merlevede  1   2   3 , Jean-Côme Meniane  8 , Christine Delaunay-Darivon  8 , Pascal Fuseau  9 , Françoise Isnard  10   11 , Nicole Casadevall  1   12 , Eric Solary  1   2   3 , Najet Debili  1   2   3 , Olivier A Bernard  1   2   3 , Hana Raslova  1   2   3 , Albert Najman  10   11 , William Vainchenker  1   2   3   4   13 , Christine Bellanné-Chantelot  1   2   3   5   11 , Isabelle Plo  1   2   3   4
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Germline duplication of ATG2B and GSKIP predisposes to familial myeloid malignancies

Joseph Saliba et al. Nat Genet. 2015 Oct.

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.

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