Mtss1 is a critical epigenetically regulated tumor suppressor in CML

• Published in: Leukemia 2016-04, Vol.30 (4), p.823-832
• Main Authors: Schemionek, M, Herrmann, O, Reher, M M, Chatain, N, Schubert, C, Costa, I G, Hänzelmann, S, Gusmao, E G, Kintsler, S, Braunschweig, T, Hamilton, A, Helgason, G V, Copland, M, Schwab, A, Müller-Tidow, C, Li, S, Holyoake, T L, Brümmendorf, T H, Koschmieder, S
• Format: Article
• Language: English
• Subjects: 13/100; 13/109; 13/21; 14; 14/19; 631/208/176/1988; 631/67/1059/602; 631/67/581; 631/67/71; 64/110; 692/699/67/1990/283/1896; Animals; Apoptosis; BCR-ABL protein; Binding sites; Blotting, Western; Bone marrow; Bone tumors; Cancer Research; Cell Movement; Cell Proliferation; Chromatin Immunoprecipitation; Chronic myeloid leukemia; CpG islands; Critical Care Medicine; Development and progression; DNA methylation; Enzyme inhibitors; Fusion protein; Fusion Proteins, bcr-abl - genetics; Gene Expression Regulation, Leukemic; Genetic aspects; Genetic regulation; Health aspects; Hematology; Hematopoietic stem cells; Humans; Intensive; Internal Medicine; Kinases; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology; Leukemogenesis; Medicine; Medicine & Public Health; Metastases; Mice; Mice, Inbred C3H; Mice, Transgenic; Microfilament Proteins - genetics; Microfilament Proteins - metabolism; Myeloid leukemia; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Oncology; original-article; Progenitor cells; Properties; Protein-tyrosine kinase; Real-Time Polymerase Chain Reaction; Remission; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Stem cell transplantation; Stem cells; Transcription factors; Transgenic mice; Tumor Cells, Cultured; Tumor suppressor genes; Tumors; Tyrosine; Xenograft Model Antitumor Assays
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2015.329

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.