Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
, 30 (4), 823-32

Mtss1 Is a Critical Epigenetically Regulated Tumor Suppressor in CML

Affiliations

Mtss1 Is a Critical Epigenetically Regulated Tumor Suppressor in CML

M Schemionek et al. Leukemia.

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.

Similar articles

See all similar articles

Cited by 9 articles

See all "Cited by" articles

References

    1. Leukemia. 2006 Jun;20(6):1035-9 - PubMed
    1. Cancer. 2007 Mar 1;109(5):899-906 - PubMed
    1. Leukemia. 2008 May;22(5):898-904 - PubMed
    1. Cancer Sci. 2006 Jan;97(1):64-71 - PubMed
    1. Br J Cancer. 2015 Mar 3;112(5):866-73 - PubMed

Publication types

MeSH terms

Feedback