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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.
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Submitted June 6, 2005
Accepted December 28, 2005
Molecular dissection of Meis1 reveals two domains required for leukemia induction and a key role for Hoxa gene activation
Aline Mamo, Jana Krosl, Evert Kroon, Janet Bijl, Alexander Thompson, Nadine Mayotte, Simon Girard, Richard Bisaillon, Nathalie Beslu, Mark Featherstone, and Guy Sauvageau*
Laboratory for Molecular Genetics of Stem Cells, Institute of Research in Immunology and Cancer (IRIC), Universite of Montreal, Montreal, Quebec, Canada
Laboratory for Molecular Genetics of Stem Cells, Institute of Research in Immunology and Cancer (IRIC), Universite of Montreal, Montreal, Quebec, Canada; Department of Haematology, Centre for Cancer Research and Cell Biology, Queen's University, Belfast, Northern Ireland
Department of Oncology, McGill Cancer Centre, McGill University, Montreal, Quebec, Canada
Laboratory for Molecular Genetics of Stem Cells, Institute of Research in Immunology and Cancer (IRIC), Universite of Montreal, Montreal, Quebec, Canada; Department of Medicine, University of Montreal, Montreal, Quebec, Canada; Division of Hematology and Leukemia Cell Bank of Quebec, Maisonneuve-Rosemont Hospital, Montreal, Quebec, Canada
* Corresponding author; email: guy.sauvageau{at}umontreal.ca.
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 three conserved domains namely, the Pbx-Interaction-Motif or PIM, the homeodomain, and the C-terminal region recently described to posses transactivating properties. Meis1 and Pbx1 interaction domain swapping mutants are dysfunctional separately, but restore the full oncogenic activity of Meis1 when co-transduced 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 harbour 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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