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PML-RAR{alpha} and Dnmt3a1 cooperate in vivo to promote acute promyelocytic leukemia.

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

SUBMITTER: Subramanyam D

PROVIDER: S-EPMC3021794 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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PML-RAR{alpha} and Dnmt3a1 cooperate in vivo to promote acute promyelocytic leukemia.

Subramanyam Deepa D Belair Cassandra D CD Barry-Holson Keegan Q KQ Lin Haijiang H Kogan Scott C SC Passegué Emmanuelle E Blelloch Robert R

Cancer research 20100921 21

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 pe ...[more]

PMID: 20861188

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