title: Essential role of PR-domain protein MDS1-EVI1 in MLL-AF9 leukemia.
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.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY; and.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Kristina
authors.initials: K
authors.lastname: Owens
authors.forename: Layla
authors.initials: L
authors.lastname: Hatem
authors.forename: Carolyn H
authors.initials: CH
authors.lastname: Glass
authors.forename: Kannan
authors.initials: K
authors.lastname: Karuppaiah
authors.forename: Fernando
authors.initials: F
authors.lastname: Camargo
authors.forename: Archibald S
authors.initials: AS
authors.lastname: Perkins
mesh_terms: D000483:Alleles; D000818:Animals; D001853:Bone Marrow / Q000473:pathology; D019070:Cell Lineage; D002471:Cell Transformation, Neoplastic; D005091:Exons; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D015456:Leukemia, Biphenotypic, Acute / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics* / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism*; D010641:Phenotype; D020033:Protein Isoforms
chemical_list: C098704:MDS1-EVI1 fusion protein, human; C490909:MDS1-EVI1 fusion protein, mouse; C474558:MLL-AF9 fusion protein, human; C551356:MLL-AF9 fusion protein, mouse; D015514:Oncogene Proteins, Fusion; D020033:Protein Isoforms; D051788:Myeloid-Lymphoid Leukemia Protein
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