Identification of the Adapter Molecule MTSS1 as a Potential Oncogene-Specific Tumor Suppressor in Acute Myeloid Leukemia

Abstract

The adapter protein metastasis suppressor 1 (MTSS1) is implicated as a tumor suppressor or tumor promoter, depending on the type of solid cancer. Here, we identified Mtss1 expression to be increased in AML subsets with favorable outcome, while suppressed in high risk AML patients. High expression of MTSS1 predicted better clinical outcome of patients with normal-karyotype AML. Mechanistically, MTSS1 expression was negatively regulated by FLT3-ITD signaling but enhanced by the AML1-ETO fusion protein. DNMT3B, a negative regulator of MTSS1, showed strong binding to the MTSS1 promoter in PML-RARA positive but not AML1-ETO positive cells, suggesting that AML1-ETO leads to derepression of MTSS1. Pharmacological treatment of AML cell lines carrying the FLT3-ITD mutation with the specific FLT3 inhibitor PKC-412 caused upregulation of MTSS1. Moreover, treatment of acute promyelocytic cells (APL) with all-trans retinoic acid (ATRA) increased MTSS1 mRNA levels. Taken together, our findings suggest that MTSS1 might have a context-dependent function and could act as a tumor suppressor, which is pharmacologically targetable in AML patients.

Role of Akt2 in regulation of metastasis suppressor 1 expression and colorectal cancer metastasis

“…Consistent with this role, expression of MTSS1 is decreased in breast, esophageal, bladder, kidney, gastric, pancreatic, ovarian and CRC, 30–33,42–47 as well as in acute and chronic myeloid leukemia, where it has been shown to function as a tumor suppressor. 48,49 Our analysis of TCGA data sets also demonstrated reduced expression of MTSS1 in human CRC tissue samples. However, a contradictory report indicating that MTSS1 over-expression increases the metastatic capacity of melanoma cells 50 points to potential functional complexity of this protein.…”

Contemporary insights into the pathogenesis and treatment of chronic myeloproliferative neoplasms

“…Interestingly, the candidacy of MTSS1 as a potent tumor suppressor has also been demonstrated in normal karyotype AML patients. [23] More recently, a novel murine model capable of simulating progression of human CML, in particular transformation to myeloid blast crisis, has been engineered. [24] This should enable a better understanding of the molecular pathogenesis of blast crisis and inform on candidate therapeutic targets.…”

Effect of metastasis suppressor 1 on H1299 cells and its clinical significance in non-small cell lung cancer

“…MTSS1 expression levels were increased in tissues adjacent to carcinoma, but clearly reduced in cancer tissues, and MTSS1 expression levels were gradually reduced as histological differentiation degree decreased (12). In the hematopoietic system, MTSS1-knockout mice had an increased propensity to develop aggressive B cell lymphomas (13,14). These studies suggested that MTSS1 acts as a tumor metastasis suppressor gene in these malignancies, that low MTSS1 expression levels confer a poorer prognosis and that higher expression levels correlate with improved overall survival rates.…”