Journal
DEVELOPMENTAL BIOLOGY
Volume 329, Issue 2, Pages 374-385Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.ydbio.2009.02.022
Keywords
Meis; Trithorax; Hox; egl-1; Apoptosis; MLL; Leukemia
Categories
Funding
- Cell and Molecular Biology Training Program [5 T32 GM008203]
- The Children's Cancer Fund
- Children's Medical Foundation
- Lauri Strauss Leukemia Foundation
- NIH [GM069667]
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Mutations that aberrantly activate trithorax-group proteins, Hox transcription factors and TALE-class Hox cofactors promote leukemogenesis, but their target genes critical for leukemogenesis remain largely unknown. Through genetic analyses in C. elegans, we find that the trithorax-group gene lin-59 and the TALE-class Hox cofactor unc-62 are required for survival of the VC motor neurons. With the goal of providing a model for how aberrantly active Hox complexes might promote leukemia, we elucidate the mechanism through which these new inhibitors of programmed cell death act: lin-59 maintains transcription of the Hox gene lin-39, while unc-62 promotes nuclear localization of the TALE-class Hox cofactor ceh-20. A LIN-39/CEH-20 complex binds the promoter of the pro-apoptotic BH3-only gene egl-1, repressing its transcription and ensuring survival of the VC neurons. In the absence of this regulatory mechanism, egl-1 is transcribed and the VC neurons die. Furthermore, ectopic expression of the Hox gene lin-39, as occurs for human Hox genes in leukemia, is sufficient to block death of some cells. This work identifies BH3-only pro-apoptotic genes as targets of Hox-mediated repression and suggests that aberrant activation of Hox networks may promote leukemia in part by inhibiting apoptosis. (C) 2009 Elsevier Inc. All rights reserved
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