PML-RARα and Dnmt3a1 Cooperate in vivo to Promote Acute Promyelocytic Leukemia

The PML-RAR alpha oncogene is the central effector of acute promyelocytic leukemia (APL). PML-RAR alpha physically interacts with epigenetic-modifying enzymes including DNA methyltransferases (Dnmt) to suppress critical downstream targets. Here, we show that increased expression of Dnmt3a1 cooperates with PML-RARa in vivo to promote early lethality secondary to myeloid expansion and dysfunction in primary mice. Bone marrow cells from these mice cause leukemogenesis with a shortened latency and a higher penetrance on transplantation into irradiated recipients. Furthermore, leukemic cells overexpressing PML-RAR alpha and Dnmt3a1 display increased methylation at a target promoter compared with PML-RARa or Dnmt3a1 controls. Our findings show a cooperation between the PML-RARa oncogene and the Dnmt3a1 enzyme in vivo and that Dnmt levels can be rate limiting in APL progression. Cancer Res; 70(21); 8792-801. (C) 2010 AACR.