title: Identification of the Adapter Molecule MTSS1 as a Potential Oncogene-Specific Tumor Suppressor in Acute Myeloid Leukemia.
abstract: The adapter protein metastasis suppressor 1 (MTSS1) is implicated as a tumor suppressor or tumor promoter, depending on the type of solid cancer. Here, we identified Mtss1 expression to be increased in AML subsets with favorable outcome, while suppressed in high risk AML patients. High expression of MTSS1 predicted better clinical outcome of patients with normal-karyotype AML. Mechanistically, MTSS1 expression was negatively regulated by FLT3-ITD signaling but enhanced by the AML1-ETO fusion protein. DNMT3B, a negative regulator of MTSS1, showed strong binding to the MTSS1 promoter in PML-RARA positive but not AML1-ETO positive cells, suggesting that AML1-ETO leads to derepression of MTSS1. Pharmacological treatment of AML cell lines carrying the FLT3-ITD mutation with the specific FLT3 inhibitor PKC-412 caused upregulation of MTSS1. Moreover, treatment of acute promyelocytic cells (APL) with all-trans retinoic acid (ATRA) increased MTSS1 mRNA levels. Taken together, our findings suggest that MTSS1 might have a context-dependent function and could act as a tumor suppressor, which is pharmacologically targetable in AML patients.
authors.affiliation: Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, Germany.
authors.forename: Mirle
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: Behzad
authors.initials: B
authors.lastname: Kharabi Masouleh
authors.affiliation: Department of Urology, University of Muenster, Muenster, Germany.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Klaile
authors.affiliation: Department of Medicine A, Hematology, Oncology, Pneumology, University of Muenster, Muenster, Germany.
authors.forename: Utz
authors.initials: U
authors.lastname: Krug
authors.affiliation: Institute for Medical Informatics, University of Muenster, Muenster, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Hebestreit
authors.affiliation: Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Schubert
authors.affiliation: Institute for Medical Informatics, University of Muenster, Muenster, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Dugas
authors.affiliation: Department of Medicine A, Hematology, Oncology, Pneumology, University of Muenster, Muenster, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Büchner
authors.affiliation: Membership of the German Society of Hematology and Oncology (DGHO), Berlin, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Wörmann
authors.affiliation: Department of Internal Medicine III, University of Munich, Munich, Germany; Clinical Cooperation Group Acute Myeloid Leukemia, Helmholtz Zentrum Munich, German Research Center for Environmental Health, Munich, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hiddemann
authors.affiliation: Department of Medicine A, Hematology, Oncology, Pneumology, University of Muenster, Muenster, Germany.
authors.forename: Wolfgang E
authors.initials: WE
authors.lastname: Berdel
authors.affiliation: Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, Germany.
authors.forename: Tim H
authors.initials: TH
authors.lastname: Brümmendorf
authors.affiliation: Department of Medicine A, Hematology, Oncology, Pneumology, University of Muenster, Muenster, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Müller-Tidow
authors.affiliation: Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Koschmieder
mesh_terms: D045744:Cell Line, Tumor; D002869:Chromosome Aberrations; D016000:Cluster Analysis; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics; D015870:Gene Expression; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D059785:Karyotype; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D008840:Microfilament Proteins / Q000235:genetics* / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D000075142:RUNX1 Translocation Partner 1 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics
chemical_list: C107844:AML1-ETO fusion protein, human; D050676:Core Binding Factor Alpha 2 Subunit; C486778:MTSS1 protein, human; D008840:Microfilament Proteins; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D047428:Protein Kinase Inhibitors; D000075142:RUNX1 Translocation Partner 1 Protein; D025521:Tumor Suppressor Proteins; D051941:fms-Like Tyrosine Kinase 3