Department of Molecular Oncology and Leukemia Program Project, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
Hiroshi Okuda
Tsuruoka Metabolomics Laboratory, National Cancer Center, Tsuruoka, Japan
Yosuke Komata
Tsuruoka Metabolomics Laboratory, National Cancer Center, Tsuruoka, Japan
Satoshi Takahashi
Tsuruoka Metabolomics Laboratory, National Cancer Center, Tsuruoka, Japan; Department of Hematology and Oncology, Kyoto University Graduate School of Medicine, Kyoto, Japan
Hirotaka Matsui
Department of Molecular Laboratory Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
Toshiya Inaba
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; Division of Hematological Malignancy, National Cancer Center Research Institute, Tokyo, Japan
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.
