Tsuruoka Metabolomics Laboratory, National Cancer Center, Tsuruoka, Japan; Department of Hematology and Oncology, Kyoto University Graduate School of Medicine, Kyoto, Japan
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
Ryo Miyamoto
Tsuruoka Metabolomics Laboratory, National Cancer Center, Tsuruoka, Japan
Yosuke Komata
Tsuruoka Metabolomics Laboratory, National Cancer Center, Tsuruoka, Japan
Takeshi Kawamura
Isotope Science Center, The University of Tokyo, Tokyo, Japan
Hirotaka Matsui
Department of Molecular Laboratory Medicine, Faculty of Life 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; Department of Hematology and Oncology, Kyoto University Graduate School of Medicine, Kyoto, Japan; Division of Hematological Malignancy, National Cancer Center Research Institute, Tokyo, Japan
Leukemic oncoproteins cause uncontrolled self-renewal of hematopoietic progenitors by aberrant gene activation, eventually causing leukemia. However, the molecular mechanism underlying aberrant gene activation remains elusive. Here, we showed that leukemic MLL fusion proteins associate with the HBO1 histone acetyltransferase (HAT) complex through their trithorax homology domain 2 (THD2) in various human cell lines. MLL proteins associated with the HBO1 complex through multiple contacts mediated mainly by the ING4/5 and PHF16 subunits in a chromatin-bound context where histone H3 lysine 4 tri-methylation marks were present. Of the many MLL fusions, MLL-ELL particularly depended on the THD2-mediated association with the HBO1 complex for leukemic transformation. The C-terminal portion of ELL provided a binding platform for multiple factors including AF4, EAF1, and p53. MLL-ELL activated gene expression in murine hematopoietic progenitors by loading an AF4/ENL/P-TEFb (AEP) complex onto the target promoters wherein the HBO1 complex promoted the association with AEP complex over EAF1 and p53. Moreover, the NUP98-HBO1 fusion protein exerted its oncogenic properties via interaction with MLL but not its intrinsic HAT activity. Thus, the interaction between the HBO1 complex and MLL is an important nexus in leukemic transformation, which may serve as a therapeutic target for drug development.
