title: SETBP1 mutations drive leukemic transformation in ASXL1-mutated MDS.
abstract: Mutations in ASXL1 are frequent in patients with myelodysplastic syndrome (MDS) and are associated with adverse survival, yet the molecular pathogenesis of ASXL1 mutations (ASXL1-MT) is not fully understood. Recently, it has been found that deletion of Asxl1 or expression of C-terminal-truncating ASXL1-MTs inhibit myeloid differentiation and induce MDS-like disease in mice. Here, we find that SET-binding protein 1 (SETBP1) mutations (SETBP1-MT) are enriched among ASXL1-mutated MDS patients and associated with increased incidence of leukemic transformation, as well as shorter survival, suggesting that SETBP1-MT play a critical role in leukemic transformation of MDS. We identify that SETBP1-MT inhibit ubiquitination and subsequent degradation of SETBP1, resulting in increased expression. Expression of SETBP1-MT, in turn, inhibited protein phosphatase 2A activity, leading to Akt activation and enhanced expression of posterior Hoxa genes in ASXL1-mutant cells. Biologically, SETBP1-MT augmented ASXL1-MT-induced differentiation block, inhibited apoptosis and enhanced myeloid colony output. SETBP1-MT collaborated with ASXL1-MT in inducing acute myeloid leukemia in vivo. The combination of ASXL1-MT and SETBP1-MT activated a stem cell signature and repressed the tumor growth factor-β signaling pathway, in contrast to the ASXL1-MT-induced MDS model. These data reveal that SETBP1-MT are critical drivers of ASXL1-mutated MDS and identify several deregulated pathways as potential therapeutic targets in high-risk MDS.
authors.affiliation: Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: D
authors.initials: D
authors.lastname: Inoue
authors.affiliation: Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Kitaura
authors.affiliation: Department of Molecular Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Matsui
authors.affiliation: Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: H-A
authors.initials: HA
authors.lastname: Hou
authors.affiliation: Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: W-C
authors.initials: WC
authors.lastname: Chou
authors.affiliation: Department of Molecular Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Nagamachi
authors.affiliation: Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: K C
authors.initials: KC
authors.lastname: Kawabata
authors.affiliation: Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Togami
authors.affiliation: Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Nagase
authors.affiliation: Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Horikawa
authors.affiliation: Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Saika
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: J-B
authors.initials: JB
authors.lastname: Micol
authors.affiliation: Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Hayashi
authors.affiliation: Department of Hematology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Harada
authors.affiliation: Department of Hematology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Harada
authors.affiliation: Department of Molecular Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Inaba
authors.affiliation: Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: H-F
authors.initials: HF
authors.lastname: Tien
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: O
authors.initials: O
authors.lastname: Abdel-Wahab
authors.affiliation: Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Kitamura
mesh_terms: D000328:Adult; D000818:Animals; D017209:Apoptosis; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015973:Gene Expression Regulation, Leukemic; D057809:HEK293 Cells; D018922:HL-60 Cells; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism; D059748:Proteolysis; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D016019:Survival Analysis; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination
chemical_list: C473949:ASXL1 protein, human; D002352:Carrier Proteins; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; C425066:SETBP1 protein, human; D016212:Transforming Growth Factor beta; C088144:HoxA protein; D051057:Proto-Oncogene Proteins c-akt; D054648:Protein Phosphatase 2