Molecular dissection of Meis1 reveals 2 domains required for leukemia induction and a key role for Hoxa gene activation
| Autor: | Janet J. Bijl, Aline Mamo, Alexander Thompson, Nathalie Beslu, Jana Krosl, Simon Girard, Guy Sauvageau, Evert Kroon, Nadine Mayotte, Mark Featherstone, Richard Bisaillon |
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| Rok vydání: | 2006 |
| Předmět: |
Transcriptional Activation
Immunology Mutant Endogeny Biology medicine.disease_cause Biochemistry Mice Transduction Genetic hemic and lymphatic diseases medicine Animals Myeloid Ecotropic Viral Integration Site 1 Protein Gene Cells Cultured Homeodomain Proteins chemistry.chemical_classification Regulation of gene expression Leukemia Herpes Simplex Virus Protein Vmw65 Histone-Lysine N-Methyltransferase Cell Biology Hematology Hematopoietic Stem Cells medicine.disease Neoplasm Proteins Protein Structure Tertiary Amino acid Cell Transformation Neoplastic chemistry Cancer research Homeobox Carcinogenesis Myeloid-Lymphoid Leukemia Protein |
| Zdroj: | Blood. 108:622-629 |
| ISSN: | 1528-0020 0006-4971 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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