medwireNews: The metastasis suppressor 1 (Mtss1) protein acts a tumour suppressor in chronic myeloid leukaemia (CML) stem cells, reveals research published in Leukemia.
Using a double transgenic mouse model of CML that expresses Bcr–Abl, the investigators demonstrated that Mtss1 was absent from leukaemic lineage-depleted progenitor cells, whereas control mice expressed high levels of the tumour suppressor.
And Mtss1 RNA expression was also found to be down regulated from blast cells taken from 76 patients at the time of CML diagnosis compared with 74 healthy donors, report Mirle Schemionek, from Universitätsklinikum der RWTH Aachen in Germany, and co-authors.
Moreover, two patients who achieved complete remission after 9 months and 12 months of TKI treatment were found to have “markedly increased” expression of Mtss1 in their blast cells. These patients had undetectable levels of Bcr–Abl at this time. This finding was repeated in two further patients.
By contrast, Mtss1 expression was absent both at baseline and after failed TKI treatment in two CML patients, of whom one developed the T315I mutation, and the other had a complex aberrant karyotype.
The researchers believe their Mtss1 results provide “a rationale for enhancing expression in CML in order to target the TKI [tyrosine kinase inhibitor]-resistant stem cell population”.
In a Bcr–Abl-positive haematopoietic cell line, Mtss1 overexpression was found to significantly affect cell motility, and when overexpressed in vivo, impaired leukaemic development and cellular homing to the spleen.
Furthermore, restoring Mtss1 expression in transgenic Bcr–Abl mice reduced leukaemic cell propagation.
While both in vitro and in vivo Bcr–Abl inhibition using TKIs led to Mtss1 upregulation, treatment did not completely restore levels of the tumour suppressor to that seen in control cells, suggesting that “Mts11 suppression might not depend exclusively on Bcr–Abl kinase activity and is not mediated via Bcr–Abl kinase-independent mechanisms of the oncogenic protein”, the authors say.
Hypothesising that Mtss1 promotor methylation may have a potential role in CML, Schemionek et al discovered that demethylation of a Bcr–Abl-positive cell line led to a threefold increase in the expression of Mtss1.
And analysis of a previously identified promotor region for Mtss1 revealed 100% methylation for 24 of the 29 CpG sites, falling to eight sites after TKI exposure. Similarly, Mtss1 promotor methylation was significantly higher in primary CML cells than healthy controls for specific CpG sites; two such sites are known to harbour binding sites for transcription factors associated with CML stem cell survival and gene silencing.
The authors note that phase II trials of the demethylating agent decitabine in CML have achieved objective responses in 63% of chronic phase patients, 55% of acute phase patients and 28% of patients in blast crisis.
While adding TKI therapy to decitabine did not increase the response rate in imatinib-refractory CML patients in acute phase or blast crisis compared with decitabine alone, the team concludes: “Our data demonstrate methylation of the Mtss1 promoter already in CML-[chronic phase] patients providing a rationale to further explore the therapeutic benefit of demethylation agents combined with TKI therapy in early phase CML.”
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