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Blood. 2013 Oct 17;122(16):2888-92. doi: 10.1182/blood-2012-08-453662. Epub 2013 Sep 10.

Essential role of PR-domain protein MDS1-EVI1 in MLL-AF9 leukemia.

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  • 1Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY; and.

Abstract

A subgroup of leukemogenic mixed-lineage leukemia (MLL) fusion proteins (MFPs) including MLL-AF9 activates the Mecom locus and exhibits extremely poor clinical prognosis. Mecom encodes EVI1 and MDS1-EVI1 (ME) proteins via alternative transcription start sites; these differ by the presence of a PRDI-BF1-RIZ1 (PR) domain with histone methyltransferase activity in the ME isoform. Using an ME-deficient mouse, we show that ME is required for MLL-AF9-induced transformation both in vitro and in vivo. And, although Nup98-HOXA9, MEIS1-HOXA9, and E2A-Hlf could transform ME-deficient cells, both MLL-AF9 and MLL-ENL were ineffective, indicating that the ME requirement is specific to MLL fusion leukemia. Further, we show that the PR domain is essential for MFP-induced transformation. These studies clearly indicate an essential role of PR-domain protein ME in MFP leukemia, suggesting that ME may be a novel target for therapeutic intervention for this group of leukemias.

PMID:
24021671
[PubMed - indexed for MEDLINE]
PMCID:
PMC3799001
Free PMC Article
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