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Blood, 15 July 2006, Vol. 108, No. 2, pp. 622-629. Prepublished online as a Blood First Edition Paper on February 9, 2006; DOI 10.1182/blood-2005-06-2244.
NEOPLASIA Molecular dissection of Meis1 reveals 2 domains required for leukemia induction and a key role for Hoxa gene activationFrom the Laboratory of Molecular Genetics of Stem Cells, Institute of Research in Immunology and Cancer (IRIC), Université de Montréal, QC, Canada; the Department of Haematology, Centre for Cancer Research and Cell Biology, Queen's University, Belfast, Northern Ireland; the Department of Oncology, McGill Cancer Centre, McGill University, Montreal, QC, Canada; the Department of Medicine, Montreal, QC, Canada; and the Division of Hematology and Leukemia Cell Bank of Quebec, Maisonneuve-Rosemont Hospital, Montreal, QC, Canada.
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.
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