Xiao-Ya Cai, Gui-Qin Huang, Ye-Ming Zhou, Deng-Ju Li
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引用次数: 0
Abstract
Objective: To investigate the effects of calprotectin (S100A8/A9) on the biological activity of acute myeloid leukemia (AML) cells harboring a DNA methyltransferase 3A (DNMT3A) mutation and to explore the underlying molecular mechanisms involved.
Methods: AML monoclonal cell lines harboring the DNMT3AR882H mutation were generated via lentiviral transduction and limiting dilution. RNA sequencing was used for differential gene expression analysis, followed by bioinformatic pathway enrichment and gene correlation analyses. The biological effects of paquinimod, a selective S100A8/A9 inhibitor, on DNMT3AR882H AML cells were assessed via Cell Counting Kit (CCK-8) proliferation assays, Annexin V/PI staining, cell cycle analysis, cell adhesion assays, and transwell migration assays.
Results: Differential gene expression analysis revealed 442 upregulated and 535 downregulated genes in DNMT3A-mutated (DNMT3Amut) cells compared with those in DNMT3A wild-type (DNMT3Awt) cells, with the S100A8/A9 complex recurrently enriched in Reactome pathway analysis. Compared with healthy controls, patients with AML presented increased expression of S100A8 and S100A9 and increased expression of DNMT3Amut cells relative to DNMT3Awt cells, which was correlated with poor prognosis in patients with AML. There were no notable differences in proliferation among the DNMT3Amut, DNMT3Awt, and empty vector cells under normal or starvation conditions. However, paquinimod treatment notably inhibited the proliferation, migration, and adhesion of DNMT3Amut AML cells in a dose-dependent manner, causing G0/G1 cell cycle arrest, whereas no significant effects on apoptosis were observed. Paquinimod also downregulated key adhesion molecules, including intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), monocyte chemoattractant protein-1 (MCP-1), and matrix metalloproteinase-2 (MMP-2). Additionally, S100A8 and S100A9 expression was upregulated in a dose-dependent manner in response to cytarabine treatment.
Conclusion: Elevated S100A8/A9 expression contributes to the abnormal proliferation, migration, adhesion, and chemoresistance of DNMT3Amut AML cells. Targeting S100A8/A9 alone or in combination with other treatments represents a promising therapeutic strategy for DNMT3Amut AML.
期刊介绍:
Current Medical Science provides a forum for peer-reviewed papers in the medical sciences, to promote academic exchange between Chinese researchers and doctors and their foreign counterparts. The journal covers the subjects of biomedicine such as physiology, biochemistry, molecular biology, pharmacology, pathology and pathophysiology, etc., and clinical research, such as surgery, internal medicine, obstetrics and gynecology, pediatrics and otorhinolaryngology etc. The articles appearing in Current Medical Science are mainly in English, with a very small number of its papers in German, to pay tribute to its German founder. This journal is the only medical periodical in Western languages sponsored by an educational institution located in the central part of China.