Laboratory studies of mice and human cells found that a protein called Metastasis suppressor 1 (Mtss1) is downregulated in hematopoietic and progenitor cells when chronic myeloid leukemia is present. Mtss1 levels are restored when complete remission is achieved, suggesting the pathway might represent a new therapeutic target.
Laboratory studies of mice and human cells found that a protein called Metastasis suppressor 1 (Mtss1) is downregulated in hematopoietic and progenitor cells when chronic myeloid leukemia (CML) is present. Mtss1 levels are restored when complete remission is achieved, suggesting the pathway might represent a new therapeutic target.
“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.