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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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NEOPLASIA
Molecular dissection of Meis1 reveals 2 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
From 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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