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.