Essential role of PR-domain protein MDS1-EVI1 in MLL-AF9 leukemia.
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.
Duke Scholars
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Related Subject Headings
- Protein Isoforms
- Phenotype
- Oncogene Proteins, Fusion
- Myeloid-Lymphoid Leukemia Protein
- Mice, Knockout
- Mice
- Leukemia, Biphenotypic, Acute
- Immunology
- Humans
- Gene Expression Regulation, Leukemic
Citation
Published In
DOI
EISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- Protein Isoforms
- Phenotype
- Oncogene Proteins, Fusion
- Myeloid-Lymphoid Leukemia Protein
- Mice, Knockout
- Mice
- Leukemia, Biphenotypic, Acute
- Immunology
- Humans
- Gene Expression Regulation, Leukemic