RRC ID 67526
Author 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, Fuseau P, Isnard F, Casadevall N, Solary E, Debili N, Bernard OA, Raslova H, Najman A, Vainchenker W, Bellanné-Chantelot C, Plo I.
Title Germline duplication of ATG2B and GSKIP predisposes to familial myeloid malignancies.
Journal Nat Genet
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.
Volume 47(10)
Pages 1131-40
Published 2015-10-1
DOI 10.1038/ng.3380
PII ng.3380
PMID 26280900
MeSH Adolescent Adult Aged Autophagy-Related Proteins Child Chromosomes, Human, Pair 14 Female Gene Duplication* Genetic Predisposition to Disease* Germ Cells* Humans Induced Pluripotent Stem Cells / cytology Infant Leukemia, Myeloid, Acute / genetics* Male Myelodysplastic Syndromes / genetics* Pedigree Phenotype Repressor Proteins / genetics* Vesicular Transport Proteins / genetics* Young Adult
IF 27.605
Human and Animal Cells OP9(RCB1124)