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.
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The authors thank Kristina Feldberg for excellent technical assistance. MS has received grant funding by the Medical Faculty, RWTH Aachen University (Start-691306-46/13). SK has received grant funding by the German Research Foundation (DFG KO 2155/2-2) and by the German José Carreras Leukemia Foundation (DJCLS grant 10/23). TH has received grant funding by the Cancer Research UK (CRUK) programme (C11074/A11008).
MS, AS, IGC, CMT, SL, TLH, THB and SK designed research. MS, OH, MMR, NC, NK, CS, SH, EGG, SKi, TB, AH, VH and MC performed research. MS, OH, IGC, AS and SK analyzed data. MS, TLH, THB and SK wrote the manuscript.
SK has received research funding from Novartis and the Novartis Foundation, provided consultancy for and participated in advisory boards for Ariad, Bristol-Myers Squibb, Novartis and Pfizer, and has received honoraria and travel grants from Ariad, Bristol-Myers Squibb, Novartis and Pfizer. MC has received research funding from Novartis and Bristol-Myers Squibb, is an advisory board member for Bristol-Myers Squibb, Novartis, Ariad and Pfizer, has received travel reimbursement from Bristol-Myers Squibb and Novartis and has received honoraria from Bristol-Myers Squibb, Novartis, Ariad and Pfizer. All other authors declare no conflict of interest.
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Schemionek, M., Herrmann, O., Reher, M. et al. Mtss1 is a critical epigenetically regulated tumor suppressor in CML. Leukemia 30, 823–832 (2016). https://doi.org/10.1038/leu.2015.329
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