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Down-regulation of MTSS1 is associated with a poor prognosis in acute myeloid leukemia and differentially affects responses to different drugs

ABSTRACT: Acute myeloid leukemia (AML) is an aggressive malignancy of hematopoietic cells. Despite recent approvals of targeted drugs, chemotherapy with cytosine arabinoside (araC) and an anthracycline like daunorubicin remains an important pillar of treatment. In a previous work, we have shown that MTSS1 is down-regulated at relapse compared to diagnosis of AML and its down-regulation was previously implicated in aggressiveness of solid tumors. Our results showed that MTSS1 expression was regulated by methylation and reduced by araC and daunorubicin. Experimental down-regulation rendered human AML cell lines more resistant to araC, daunorubicin, and eight additional drugs. In contrast, venetoclax, a BCL2 inhibitor, was more effective towards cells with low MTSS1 expression. A CRISPR/Cas9-mediated knock-out of the MTSS1 gene was used to generate insight into the molecular changes induced by the down-regulation of MTSS1. The knock-out led to the deregulation of > 900 genes which included numerous target genes of transcription factors with a confirmed role in hematopoiesis and AML. A gene ontology analysis of the differentially expressed genes revealed that genes linked to transcription, cell cycle, and immune response were strongly affect. In summary, down-regulation of MTSS1 is associated with primary and secondary chemotherapy resistance in AML. In experimental models, it confers refractoriness to several cytotoxic drugs, yet sensitizes cells to venetoclax, pointing towards ways to overcome therapy resistance in MTSS1low AML.

ORGANISM(S): Homo sapiens

PROVIDER: GSE152239 | GEO | 2021/03/25

REPOSITORIES: GEO

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Project description:Hepatectomy generally offers the best chance of long-term survival for patients with hepatocellular carcinoma (HCC). Many studies have shown that hepatectomy accelerates tumor metastasis, but the mechanism remains unclear. In this study, palliative hepatectomy was performed in an orthotopic nude mice model of HCC (MHCC97H) with high metastatic potential. Using Human Tumor Metastasis Microarray, we screened the metastasis-related genes in tumor tissues following palliative resection, and found that Metastasis suppressor 1 (MTSS1) located in the central position of gene function net of residual HCC; MTSS1 was up-regulated in residual tumor after palliative resection. Further studies found that MTSS1 enhanced the metastasis of residual HCC. In hepatitis B-related HCC patients undergone palliative hepatectomy, those with higher MTSS1 mRNA expression accompanied by the activation of matrix metalloproteinase 2 (MMP2) in residual HCC, had earlier residual HCC detection after hepatectomy and poorer survival when compared to those with lower MTSS1 level. In different cell lines, the levels of MTSS1 mRNA increased in parallel with metastatic potential. MTSS1 down regulation via siRNA decreased MMP2 activity, reduced invasive potentials of HCC by 28.9% in vitro, and averted the deteriorated lung metastatic extent in vivo. In conclusion, the poor prognosis of hepatitis B-related HCC patients following palliative hepatectomy associates with elevated MTSS1 mRNA expression; therefore, MTSS1 may provide a new research field for HCC diagnosis and treatment. Eighteen nude mice bearing HCC xenografts were randomized into three groups 14 days after orthotopic implantation: palliative resection group (mice received partial HCC resection with preservation of 2 mm tumor pedicles), sham operation group (mice only undergone an exposure of liver but without resection), and blank control group (mice without further surgical intervention). All mice were sacrificed by cervical dislocation 14 days following palliative resection based on pre-experimental results. The first time surgically removed HCC tissues were named tumor tissues T1; the second time surgically removed HCC tissues from sham operation group were named tumor tissues T2; Tissues from blank control group were named tumor tissues T3; Tissues from palliative resection group were named tumor tissues T4 that was residual HCC. Randomly selected 5 tumor specimens from each group were used for the screen of genes related to metastasis by microarray techniques.

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Down-regulation of MTSS1 is associated with a poor prognosis in acute myeloid leukemia and differentially affects responses to different drugs

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