Enforced differentiation of Dnmt3a-null bone marrow leads to failure with c-Kit mutations driving leukemic transformation.

ABSTRACT: Genome sequencing studies of patient samples have implicated the involvement of various components of the epigenetic machinery in myeloid diseases, including the de novo DNA methyltransferase DNMT3A. We have recently shown that Dnmt3a is essential for hematopoietic stem cell differentiation. Here, we investigated the effect of loss of Dnmt3a on hematopoietic transformation by forcing the normally quiescent hematopoietic stem cells to divide in vivo. Mice transplanted with Dnmt3a-null bone marrow in the absence of wildtype support cells succumbed to bone marrow failure (median survival, 328 days) characteristic of myelodysplastic syndromes with symptoms including anemia, neutropenia, bone marrow hypercellularity, and splenomegaly with myeloid infiltration. Two out of 25 mice developed myelo

SUBMITTER: Celik H 

PROVIDER: S-EPMC4304107 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature