BioProject

Loss of function mutations in the DNA methyltransferase DNMT3A are highly recurrent in acute myeloid leukemia (AML). More...

Loss of function mutations in the DNA methyltransferase DNMT3A are highly recurrent in acute myeloid leukemia (AML). DNMT3A and DNMT3B encode the two methyltransferases that are primarily responsible for the de novo methylation of specific DNA sequences during cellular differentiation. DNMT3A mutations are rarely found in AML patients with translocations that create oncogenic fusion genes (e.g. PML-RARA, RUNX1-RUNX1T1, CBFB-MYH11, and MLL-X). To begin to define the reasons why these mutations do not occur together, we used retroviral vectors to express PML-RARA, RUNX1-RUNX1T1, and MLL-AF9 in the bone marrow cells of wild type (WT) or Dnmt3a deficient mice; we also examined the hematopoietic phenotypes of Ctsg-PML-RARA animals (which express PML-RARA in early hematopoietic progenitors and myeloid precursors) with and without Dnmt3a. We demonstrated that the methyltransferase activity of Dnmt3a (but not Dnmt3b) is required for aberrant self-renewal ex vivo that is driven by PML-RARA (but not RUNX1-RUNX1T1 or MLL-AF9); furthermore, the PML-RARA-driven competitive transplantation advantage and leukemia generation both required Dnmt3a. Together, these findings demonstrate that PML-RARA is specifically dependent on Dnmt3a to initiate APL in mice, and may explain why loss-of-function DNMT3A mutations are not found in patients with acute promyelocytic leukemia. Overall design: Samples were specific sorted progenitor populations (CMP, common myeloid progenitors; GMP, granulocyte-monocyte progenitor) isolated from wild-type or Dnmt3a-/- mice on the C57Bl/6J background. Less...