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Leukemia. 2016 Apr;30(4):823-32. doi: 10.1038/leu.2015.329. Epub 2015 Dec 1.

Mtss1 is a critical epigenetically regulated tumor suppressor in CML.

Author information

1
Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, Germany.
2
IZKF Research Group Bioinformatics, Institute for Biomedical Engineering, RWTH Aachen University, Aachen, Germany.
3
Institute of Pathology, Faculty of Medicine, RWTH Aachen University, Aachen, Germany.
4
Haematopoietic Stem Cell Laboratory, London Research Institute, Cancer Research UK, London, UK.
5
Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
6
Institute of Physiology II, University of Münster, Münster, Germany.
7
Department of Hematology and Oncology, University of Halle, Halle, Germany.
8
University of Massachusetts Medical School, Worcester, MA, USA.

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.

PMID:
26621336
DOI:
10.1038/leu.2015.329
[Indexed for MEDLINE]

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