HHEX promotes myeloid transformation in cooperation with mutant ASXL1.

Autor:	Takeda R; Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan., Asada S; Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.; The Institute of Laboratory Animals, Tokyo Women's Medical University, Tokyo, Japan., Park SJ; Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan., Yokoyama A; National Cancer Center Tsuruoka Metabolomics Laboratory, Yamagata, Japan., Becker HJ; Division of Stem Cell Biology, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan., Kanai A; Department of Molecular Oncology and Leukemia Program Project, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan., Visconte V; Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, and., Hershberger C; Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH., Hayashi Y; Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.; Department of Hematology-Oncology, Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation at Kobe, Kobe, Japan., Yonezawa T; Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan., Tamura M; Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan., Fukushima T; Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan., Tanaka Y; Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan., Fukuyama T; Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan., Matsumoto A; Laboratory of Molecular Medicine, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; and., Yamasaki S; Laboratory of Molecular Medicine, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; and., Nakai K; Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan., Yamazaki S; Division of Stem Cell Biology, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.; Department of Stem Cell Therapy, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan., Inaba T; Department of Molecular Oncology and Leukemia Program Project, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan., Shibata T; Laboratory of Molecular Medicine, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; and., Inoue D; Department of Hematology-Oncology, Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation at Kobe, Kobe, Japan., Honda H; The Institute of Laboratory Animals, Tokyo Women's Medical University, Tokyo, Japan., Goyama S; Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan., Maciejewski JP; Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, and., Kitamura T; Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.; Department of Hematology-Oncology, Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation at Kobe, Kobe, Japan.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2020 Oct 01; Vol. 136 (14), pp. 1670-1684.
DOI:	10.1182/blood.2019004613
Abstrakt:	Additional sex combs-like 1 (ASXL1), an epigenetic modulator, is frequently mutated in myeloid neoplasms. Recent analyses of mutant ASXL1 conditional knockin (ASXL1-MT-KI) mice suggested that ASXL1-MT alone is insufficient for myeloid transformation. In our previous study, we used retrovirus-mediated insertional mutagenesis, which exhibited the susceptibility of ASXL1-MT-KI hematopoietic cells to transform into myeloid leukemia cells. In this screening, we identified the hematopoietically expressed homeobox (HHEX) gene as one of the common retrovirus integration sites. In this study, we investigated the potential cooperation between ASXL1-MT and HHEX in myeloid leukemogenesis. Expression of HHEX enhanced proliferation of ASXL1-MT-expressing HSPCs by inhibiting apoptosis and blocking differentiation, whereas it showed only modest effect in normal HSPCs. Moreover, ASXL1-MT and HHEX accelerated the development of RUNX1-ETO9a and FLT3-ITD leukemia. Conversely, HHEX depletion profoundly attenuated the colony-forming activity and leukemogenicity of ASXL1-MT-expressing leukemia cells. Mechanistically, we identified MYB and ETV5 as downstream targets for ASXL1-MT and HHEX by using transcriptome and chromatin immunoprecipitation-next-generation sequencing analyses. Moreover, we found that expression of ASXL1-MT enhanced the binding of HHEX to the promoter loci of MYB or ETV5 via reducing H2AK119ub. Depletion of MYB or ETV5 induced apoptosis or differentiation in ASXL1-MT-expressing leukemia cells, respectively. In addition, ectopic expression of MYB or ETV5 reversed the reduced colony-forming activity of HHEX-depleted ASXL1-MT-expressing leukemia cells. These findings indicate that the HHEX-MYB/ETV5 axis promotes myeloid transformation in ASXL1-mutated preleukemia cells. (© 2020 by The American Society of Hematology.)
Databáze:	MEDLINE
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