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

Institute for Regeneration Medicine, University of California, San Francisco, California 94143, USA.
Cancer Research (Impact Factor: 9.33). 11/2010; 70(21):8792-801. DOI: 10.1158/0008-5472.CAN-08-4481
Source: PubMed


The PML-RARα oncogene is the central effector of acute promyelocytic leukemia (APL). PML-RARα 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-RARα 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-RARα and Dnmt3a1 display increased methylation at a target promoter compared with PML-RARα or Dnmt3a1 controls. Our findings show a cooperation between the PML-RARα oncogene and the Dnmt3a1 enzyme in vivo and that Dnmt levels can be rate limiting in APL progression.

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    • "Consistently, APL patients are characterised by a specific DNA methylation pattern that is distinctive from other AML subtypes (Figueroa et al, 2010). More importantly, overexpression of the DNMT3a collaborates with PML–RARalpha to promote APL leukaemogenesis in vivo (Subramanyam et al, 2010), and aberrant DNA methylation in p15 and p16 genes has negative prognostic impact in APL patients (Chim et al, 2001; Teofili et al, 2003), suggesting a critical role of aberrant DNA methylation in APL pathogenesis. However, recent global epigenetic analyses revealed that ATRA treatment induced major changes in post-translational modifications such as histone acetylation, but not DNA methylation in APL cells (Martens et al, 2010; Mikesch et al, 2010). "
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