Targeting Calprotectin S100A8/A9 to Overcome AML Progression in DNMT3A-Mutant Cells.

IF 2 4区 医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL
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.

靶向钙保护蛋白S100A8/A9在dnmt3a突变细胞中克服AML进展
目的:研究钙保护蛋白(S100A8/A9)对DNA甲基转移酶3A (DNMT3A)突变的急性髓系白血病(AML)细胞生物活性的影响,并探讨其潜在的分子机制。方法:通过慢病毒转导和限制性稀释制备含有DNMT3AR882H突变的AML单克隆细胞系。采用RNA测序进行差异基因表达分析,然后进行生物信息学途径富集和基因相关性分析。通过细胞计数试剂盒(CCK-8)增殖试验、Annexin V/PI染色、细胞周期分析、细胞粘附试验和跨井迁移试验评估paquinimod(选择性S100A8/A9抑制剂)对DNMT3AR882H AML细胞的生物学效应。结果:差异基因表达分析显示,与DNMT3A野生型(DNMT3Awt)细胞相比,DNMT3A突变(DNMT3Amut)细胞中有442个基因上调,535个基因下调,Reactome通路分析中S100A8/A9复合体反复富集。与健康对照组相比,AML患者S100A8、S100A9表达增高,DNMT3Amut细胞相对于DNMT3Awt细胞表达增高,与AML患者预后不良相关。DNMT3Amut、DNMT3Awt和空载体细胞在正常或饥饿条件下的增殖无显著差异。然而,帕喹尼莫德治疗显著抑制DNMT3Amut AML细胞的增殖、迁移和粘附,并呈剂量依赖性,导致G0/G1细胞周期阻滞,而对细胞凋亡无明显影响。帕喹尼莫德还下调了关键粘附分子,包括细胞间粘附分子1 (ICAM-1)、血管细胞粘附分子1 (VCAM-1)、单核细胞趋化蛋白-1 (MCP-1)和基质金属蛋白酶-2 (MMP-2)。此外,S100A8和S100A9的表达在阿糖胞苷治疗后呈剂量依赖性上调。结论:S100A8/A9表达升高与DNMT3Amut AML细胞的异常增殖、迁移、粘附和化疗耐药有关。单独靶向S100A8/A9或联合其他治疗方法是治疗DNMT3Amut AML的一种有前景的治疗策略。
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来源期刊
Current Medical Science
Current Medical Science Biochemistry, Genetics and Molecular Biology-Genetics
CiteScore
4.70
自引率
0.00%
发文量
126
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.
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