PML-RAR{alpha} and Dnmt3a1 cooperate in vivo to promote acute promyelocytic leukemia.
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.
Subramanyam
Deepa
D
Institute for Regeneration Medicine, University of California, San Francisco, California 94143, USA.
Belair
Cassandra D
CD
Barry-Holson
Keegan Q
KQ
Lin
Haijiang
H
Kogan
Scott C
SC
Passegué
Emmanuelle
E
Blelloch
Robert
R
D000818:Animals; D001854:Bone Marrow Cells / Q000473:pathology; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D005434:Flow Cytometry; D005804:Genes, Lethal; D006801:Humans; D007249:Inflammation / Q000209:etiology / Q000473:pathology; D015473:Leukemia, Promyelocytic, Acute / Q000209:etiology* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D016897:Respiratory Burst; D015996:Survival Rate
C000717967:DNMT3A protein, human; D015514:Oncogene Proteins, Fusion; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A