HOXA9 promotes MYC-mediated leukemogenesis by maintaining gene expression for multiple anti-apoptotic pathways

eLife

Hirotaka Matsui¹  Toshiya Inaba²  Akinori Kanai²  Ryo Miyamoto³  Hiroshi Okuda³  Yosuke Komata³  Satoshi Takahashi⁴  Akihiko Yokoyama⁵ 

[1] Department of Molecular Laboratory Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan;Department of Molecular Oncology and Leukemia Program Project, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan;Tsuruoka Metabolomics Laboratory, National Cancer Center, Tsuruoka, Japan;Tsuruoka Metabolomics Laboratory, National Cancer Center, Tsuruoka, Japan;Department of Hematology and Oncology, Kyoto University Graduate School of Medicine, Kyoto, Japan;Tsuruoka Metabolomics Laboratory, National Cancer Center, Tsuruoka, Japan;Division of Hematological Malignancy, National Cancer Center Research Institute, Tokyo, Japan;

关键词: HOXA9;    MYC;    leukemia;    apoptosis;    transcription;    Mouse;   

DOI  :  10.7554/eLife.64148

来源: eLife Sciences Publications, Ltd

【 摘 要 】

HOXA9 is often highly expressed in leukemias. However, its precise roles in leukemogenesis remain elusive. Here, we show that HOXA9 maintains gene expression for multiple anti-apoptotic pathways to promote leukemogenesis. In MLL fusion-mediated leukemia, MLL fusion directly activates the expression of MYC and HOXA9. Combined expression of MYC and HOXA9 induced leukemia, whereas single gene transduction of either did not, indicating a synergy between MYC and HOXA9. HOXA9 sustained expression of the genes implicated in the hematopoietic precursor identity when expressed in hematopoietic precursors, but did not reactivate it once silenced. Among the HOXA9 target genes, BCL2 and SOX4 synergistically induced leukemia with MYC. Not only BCL2, but also SOX4 suppressed apoptosis, indicating that multiple anti-apoptotic pathways underlie cooperative leukemogenesis by HOXA9 and MYC. These results demonstrate that HOXA9 is a crucial transcriptional maintenance factor that promotes MYC-mediated leukemogenesis, potentially explaining why HOXA9 is highly expressed in many leukemias.

【 授权许可】

CC BY