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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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Project description:The physiologic actions of retinoic acids (RAs) are mediated through RA receptors (RARs) and retinoid X receptors (RXRs). The RAR(alpha) gene has drawn particular attention because it is the common target in all chromosomal translocations in acute promyelocytic leukemia (APL), a unique model in cancer research that responds to the effect of RA. In the great majority of patients with APL, RAR(alpha) is fused to the PML gene as a result of the t(15;17) translocation. Three distinct types of PML-RAR(alpha) transcripts, long (L), short (S), and variant (V), were identified. The V-type is characterized by truncation of exon 6 of PML and in some cases by the insertion of a variable "spacer" sequence between the truncated PML and RAR(alpha) mRNA fusion partners, although the precise mechanisms underlying formation of the V-type transcript remain unclear. To get further insights into the molecular basis of the t(15;17), we sequenced the entire genomic DNA region of RAR(alpha). Of note, all previously reported "spacer" sequences in V-type transcripts were found in intron 2 of the RAR(alpha) gene and most of these sequences were flanked by gt splice donor sites. In most cases, these "cryptic" coding sequences maintained the ORF of the chimeric transcript. Interestingly, two cases with a relatively long spacer sequence showed APL cellular and clinical resistance to RA treatment. In these cases, the aberrant V-type PML-RAR(alpha) protein displayed increased affinity to the nuclear corepressor protein SMRT, providing further evidence that RA exerts the therapeutic effect on APL through modulation of the RAR-corepressor interaction. Finally, among patients with the L- or S-type PML-RAR(alpha) fusion transcript, some consensus motifs were identified at the hotspots of the chromosome 17q breakpoints within intron 2 of RAR(alpha), strengthening the importance of this intron in the molecular pathogenesis of APL.

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