Essential role of PR-domain protein MDS1-EVI1 in MLL-AF9 leukemia
| Autor: | Carolyn Glass, Kannan Karuppaiah, Yi Zhang, Kristina Owens, Fernando D. Camargo, Layla Hatem, Archibald S. Perkins |
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| Rok vydání: | 2013 |
| Předmět: |
Gene isoform
Histone methyltransferase activity Oncogene Proteins MECOM Oncogene Proteins Fusion Immunology Protein domain Biology Biochemistry Leukemogenic Mice Bone Marrow hemic and lymphatic diseases medicine Animals Humans Protein Isoforms Cell Lineage neoplasms Alleles Mice Knockout Myeloid Neoplasia Gene Expression Regulation Leukemic Cell Biology Hematology Exons medicine.disease Molecular biology Fusion protein Cell biology Leukemia Biphenotypic Acute Leukemia Cell Transformation Neoplastic Phenotype Myeloid-Lymphoid Leukemia Protein |
| Zdroj: | Blood. 122(16) |
| ISSN: | 1528-0020 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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