MTSS1 Protein May Act As Tumor Suppressor, Downregulated in CML

“Genetically, disease progression is associated with the acquisition of further chromosomal aberrations or mutations,” wrote study authors led by Mirle Schemionek, PhD, of University Hospital RWTH Aachen in Germany. “At the epigenetic level, DNA promoter methylation of specific genes, often tumor suppressors, has been associated with disease progression.”

Previous work has shown that Mtss1 has a tumor suppressive function in various cancers. In this new study, the researchers examined Mtss1 expression in transgenic mice and in human CML cells. The results were published online ahead of print in Leukemia.

In a mouse model that the authors wrote “closely reflects human CML,” Mtss1 expression was downregulated by 2.35-fold. The protein was totally absent in leukemic progenitor cells when mice were induced to express Bcr-Abl, while high Mtss1 expression levels were seen in three out of four control mice. In a second set of CML mice the downregulation was found to be even higher, at 5.8-fold compared to controls.

This was confirmed in cell samples from human CML patients. At the time of diagnosis, MTSS1 was completely absent in all patients studied. In two patients who achieved complete remission after tyrosine kinase inhibitor (TKI) therapy, MTSS1 expression was substantially higher after 9 and 12 months.

The researchers also tested whether overexpression of Mtss1 could limit leukemic cell growth, and found that it did in mice. They noted that restored expression of the protein “markedly” decreased leukemic cell propagation without enhancing differentiation of myeloid cells. Inhibition of Bcr-Abl in mice did raise expression levels of Mtss1, though not to control levels. This suggests that Mtss1 may not depend exclusively on Bcr-Abl kinase activity.

Finally, the researchers found that methylation of DNA promoter sites likely plays a role in downregulation of Mtss1, though the exact mechanism of this process is still unclear.

“We demonstrate that Mtss1 functions as a tumor suppressor in CML, providing a rationale for enhancing Mtss1 expression in CML in order to target the TKI-resistant stem cell population,” they authors concluded.

- See more at: http://www.cancernetwork.com/chronic-myeloid-leukemia/mtss1-protein-may-act-tumor-suppressor-downregulated-cml?GUID=973F492C-B60B-476A-9B20-E1B81DF4EDE9&XGUID=&rememberme=1&ts=16022016

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As published online ahead of print in 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.

http://www.nature.com/leu/journal/vaop/ncurrent/abs/leu2015329a.html