MTSS1 is a critical epigenetically regulated tumor suppressor in CML

Schemionek, M. et al. (2016) MTSS1 is a critical epigenetically regulated tumor suppressor in CML. Leukemia, 30(4), pp. 823-830. (doi:10.1038/leu.2015.329) (PMID:26621336)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Holyoake, Professor Tessa and Helgason, Dr Vignir and Copland, Professor Mhairi
Authors: Schemionek, M., Herrmann, O., Merle Reher, M., Chatain, N., Schubert, C., Costa, I. G., Haenzelmann, 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., and Koschmieder, S.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Leukemia
Publisher:Nature Publishing Group
ISSN:0887-6924
ISSN (Online):1476-5551
Published Online:19 January 2016
Copyright Holders:Copyright © 2015 Nature Publishing Group
First Published:First published in Leukemia 30(4):823-830
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher.

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
498551Key survival pathways in chronic myeloid leukaemia (cml) stem cells and novel approaches to their eradicationTessa HolyoakeCancer Research UK (CAN-RES-UK)11008RI CANCER SCIENCES
498552Key survival pathways in chronic myeloid leukaemia (cml) stem cells and novel approaches to their eradicationTessa HolyoakeCancer Research UK (CAN-RES-UK)11008RI CANCER SCIENCES
506531An investigation of the control of cell division and quiescence in leukaemic versus normal haemopoietic stem and progenitor cellsMhairi CoplandScottish Executive Health Department (SEHHD-CSO)SCD/04RI CANCER SCIENCES