title: Mtss1 is a critical epigenetically regulated tumor suppressor in CML.
abstract: Chronic myeloid leukemia (CML) is driven by malignant stem cells that can persist despite therapy. We have identified Metastasis suppressor 1 (Mtss1/MIM) to be downregulated in hematopoietic stem and progenitor cells from leukemic transgenic SCLtTA/Bcr-Abl mice and in patients with CML at diagnosis, and Mtss1 was restored when patients achieved complete remission. Forced expression of Mtss1 decreased clonogenic capacity and motility of murine myeloid progenitor cells and reduced tumor growth. Viral transduction of Mtss1 into lineage-depleted SCLtTA/Bcr-Abl bone marrow cells decreased leukemic cell burden in recipients, and leukemogenesis was reduced upon injection of Mtss1-overexpressing murine myeloid 32D cells. Tyrosine kinase inhibitor (TKI) therapy and reversion of Bcr-Abl expression increased Mtss1 expression but failed to restore it to control levels. CML patient samples revealed higher DNA methylation of specific Mtss1 promoter CpG sites that contain binding sites for Kaiso and Rest transcription factors. In summary, we identified a novel tumor suppressor in CML stem cells that is downregulated by both Bcr-Abl kinase-dependent and -independent mechanisms. Restored Mtss1 expression markedly inhibits primitive leukemic cell biology in vivo, providing a therapeutic rationale for the Bcr-Abl-Mtss1 axis to target TKI-resistant CML stem cells in patients.
authors.affiliation: Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Schemionek
authors.affiliation: Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, Germany.
authors.forename: O
authors.initials: O
authors.lastname: Herrmann
authors.affiliation: Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, Germany.
authors.forename: M M
authors.initials: MM
authors.lastname: Reher
authors.affiliation: Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Chatain
authors.affiliation: Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Schubert
authors.affiliation: IZKF Research Group Bioinformatics, Institute for Biomedical Engineering, RWTH Aachen University, Aachen, Germany.
authors.forename: I G
authors.initials: IG
authors.lastname: Costa
authors.affiliation: IZKF Research Group Bioinformatics, Institute for Biomedical Engineering, RWTH Aachen University, Aachen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Hänzelmann
authors.affiliation: IZKF Research Group Bioinformatics, Institute for Biomedical Engineering, RWTH Aachen University, Aachen, Germany.
authors.forename: E G
authors.initials: EG
authors.lastname: Gusmao
authors.affiliation: Institute of Pathology, Faculty of Medicine, RWTH Aachen University, Aachen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Kintsler
authors.affiliation: Institute of Pathology, Faculty of Medicine, RWTH Aachen University, Aachen, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Braunschweig
authors.affiliation: Haematopoietic Stem Cell Laboratory, London Research Institute, Cancer Research UK, London, UK.
authors.forename: A
authors.initials: A
authors.lastname: Hamilton
authors.affiliation: Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
authors.forename: G V
authors.initials: GV
authors.lastname: Helgason
authors.affiliation: Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
authors.forename: M
authors.initials: M
authors.lastname: Copland
authors.affiliation: Institute of Physiology II, University of Münster, Münster, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Schwab
authors.affiliation: Department of Hematology and Oncology, University of Halle, Halle, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Müller-Tidow
authors.affiliation: University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Li
authors.affiliation: Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
authors.forename: T L
authors.initials: TL
authors.lastname: Holyoake
authors.affiliation: Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, Germany.
authors.forename: T H
authors.initials: TH
authors.lastname: Brümmendorf
authors.affiliation: Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Koschmieder
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002465:Cell Movement; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D008809:Mice, Inbred C3H; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C486778:MTSS1 protein, human; D008840:Microfilament Proteins; C473219:Mtss1 protein, mouse; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D016044:Fusion Proteins, bcr-abl