Molecular Dissection of Meis1 Reveals 2 Domains Required for Leukemia Induction and a Key Role for Hoxa Gene Activation.
From: Laboratory of Molecular Genetics of Stem Cells, Institute of Research in Immunology and Cancer (IRIC), Université de Montréal, QC, Canada.
Blood
- Publish Date: Jul 2006
- ISSN: 0006-4971
- Volume: 108
- Issue: 2
- Pages: 622-9
- Medium: Print
- Language: English
- Citation (JAMA): Mamo Aline, Krosl Jana, Kroon Evert, et al. Molecular Dissection of Meis1 Reveals 2 Domains Required for Leukemia Induction and a Key Role for Hoxa Gene Activation.. Blood Jul 2006;108:622-9
Abstract
The Hoxa9 and Meis1 genes represent important oncogenic collaborators activated in a significant proportion of human leukemias with genetic alterations in the MLL gene. In this study, we show that the transforming property of Meis1 is modulated by 3 conserved domains, namely the Pbx interaction motif (PIM), the homeodomain, and the C-terminal region recently described to possess transactivating properties. Meis1 and Pbx1 interaction domain-swapping mutants are dysfunctional separately, but restore the full oncogenic activity of Meis1 when cotransduced in primary cells engineered to overexpress Hoxa9, thus implying a modular nature for PIM in Meis1-accelerated transformation. Moreover, we show that the transactivating domain of VP16 can restore, and even enhance, the oncogenic potential of the Meis1 mutant lacking the C-terminal 49 amino acids. In contrast to Meis1, the fusion VP16-Meis1 is spontaneously oncogenic, and all leukemias harbor genetic activation of endogenous Hoxa9 and/or Hoxa7, suggesting that Hoxa gene activation represents a key event required for the oncogenic activity of VP16-Meis1.
Mesh Headings (Keywords): Animals, Cell Transformation, Neoplastic, Cells, Cultured, Hematopoietic Stem Cells, Herpes Simplex Virus Protein Vmw65, Homeodomain Proteins, Leukemia, Mice, Myeloid-Lymphoid Leukemia Protein, Neoplasm Proteins, Protein Structure, Tertiary, Trans-Activation (Genetics), Transduction, Genetic
Check for Full Text / PubMed Unique Identifier (PMID): 16469876
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