Identification of the Adapter Molecule MTSS1 as a Potential Oncogene-Specific Tumor Suppressor in Acute Myeloid Leukemia

Mirle Schemionek; Behzad Kharabi Masouleh; Yvonne Klaile; Utz Krug; Katja Hebestreit; Claudia Schubert; Martin Dugas; Thomas Büchner; Bernhard Wörmann; Wolfgang Hiddemann; Wolfgang E Berdel; Tim H Brümmendorf; Carsten Müller-Tidow; Steffen Koschmieder

doi:10.1371/journal.pone.0125783

Identification of the Adapter Molecule MTSS1 as a Potential Oncogene-Specific Tumor Suppressor in Acute Myeloid Leukemia

PLoS One. 2015 May 21;10(5):e0125783. doi: 10.1371/journal.pone.0125783. eCollection 2015.

Affiliations

¹ Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, Germany.
² Department of Urology, University of Muenster, Muenster, Germany.
³ Department of Medicine A, Hematology, Oncology, Pneumology, University of Muenster, Muenster, Germany.
⁴ Institute for Medical Informatics, University of Muenster, Muenster, Germany.
⁵ Membership of the German Society of Hematology and Oncology (DGHO), Berlin, Germany.
⁶ 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.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Line, Tumor
Chromosome Aberrations
Cluster Analysis
Core Binding Factor Alpha 2 Subunit / genetics
Gene Expression
Gene Expression Profiling
Gene Expression Regulation, Leukemic / drug effects
Humans
Karyotype
Leukemia, Myeloid, Acute / genetics*
Leukemia, Myeloid, Acute / metabolism
Leukemia, Myeloid, Acute / mortality
Microfilament Proteins / genetics*
Microfilament Proteins / metabolism
Neoplasm Proteins / genetics*
Neoplasm Proteins / metabolism
Oncogene Proteins, Fusion / genetics
Prognosis
Protein Kinase Inhibitors / pharmacology
RUNX1 Translocation Partner 1 Protein
Tumor Suppressor Proteins / genetics
Tumor Suppressor Proteins / metabolism
fms-Like Tyrosine Kinase 3 / genetics

Substances

AML1-ETO fusion protein, human
Core Binding Factor Alpha 2 Subunit
MTSS1 protein, human
Microfilament Proteins
Neoplasm Proteins
Oncogene Proteins, Fusion
Protein Kinase Inhibitors
RUNX1 Translocation Partner 1 Protein
Tumor Suppressor Proteins
fms-Like Tyrosine Kinase 3

Grants and funding

Steffen Koschmieder has received grant funding from the German Research Foundation (DFG KO 2155/2-2) and the German José Carreras Leukemia Foundation (DJCLS grant 10/23). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.