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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. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: 2005-06-2244v1 108/2/622    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Mamo, A. Articles by Sauvageau, G. Search for Related Content PubMed PubMed Citation Articles by Mamo, A. Articles by Sauvageau, G. Related Collections Oncogenes and Tumor Suppressors Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: B. Argiropoulos, E. Yung, and R. K. Humphries Unraveling the crucial roles of Meis1 in leukemogenesis and normal hematopoiesis Genes & Dev., November 15, 2007; 21(22): 2845 - 2849. [Full Text] [PDF] G. Jin, Y. Yamazaki, M. Takuwa, T. Takahara, K. Kaneko, T. Kuwata, S. Miyata, and T. Nakamura Trib1 and Evi1 cooperate with Hoxa and Meis1 in myeloid leukemogenesis Blood, May 1, 2007; 109(9): 3998 - 4005. [Abstract] [Full Text] [PDF] D. Bansal, C. Scholl, S. Frohling, E. McDowell, B. H. Lee, K. Dohner, P. Ernst, A. J. Davidson, G. Q. Daley, L. I. Zon, et al. Cdx4 dysregulates Hox gene expression and generates acute myeloid leukemia alone and in cooperation with Meis1a in a murine model PNAS, November 7, 2006; 103(45): 16924 - 16929. [Abstract] [Full Text] [PDF]

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