Fat Mass and Obesity-Associated Protein-Mediated Adipogenic Differentiation of Bone Marrow Mesenchymal Stem Cells Promotes Chemotherapy Resistance in Acute Myeloid Leukemia.

IF 3.8 4区 医学 Q2 MEDICINE, GENERAL & INTERNAL
Pan Zhipeng, Kang Lixia, Chen Ling
{"title":"Fat Mass and Obesity-Associated Protein-Mediated Adipogenic Differentiation of Bone Marrow Mesenchymal Stem Cells Promotes Chemotherapy Resistance in Acute Myeloid Leukemia.","authors":"Pan Zhipeng, Kang Lixia, Chen Ling","doi":"10.4274/balkanmedj.galenos.2025.2025-7-150","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Chemotherapy resistance and relapse in acute myeloid leukemia (AML) are associated with poor prognosis. Bone marrow mesenchymal stem cells (MSCs) show enhanced adipogenic differentiation in AML, which may contribute to chemoresistance; however, the underlying mechanisms remain incompletely understood.</p><p><strong>Aims: </strong>To investigate how adipogenic differentiation of MSCs from chemotherapy-resistant AML patients (CR-AML-MSCs) promotes chemoresistance, focusing on the roles of the fat mass and obesity-associated protein (FTO) and the mTORC1 pathway.</p><p><strong>Study design: </strong>Experimental study.</p><p><strong>Methods: </strong>This study compared bone marrow MSCs from chemotherapy-sensitive (CS) and CR AML patients. Adipogenic differentiation was assessed using Oil Red O staining. RNA sequencing, qPCR, and western blotting were employed to analyze expression of FTO, Raptor, and PPARγ. Global m<sup>6</sup>A levels were measured, and co-culture models with AML cell lines (U937, HL-60, THP-1) were established to evaluate chemoresistance. Gain- and loss-of-function experiments for FTO were performed using lentiviral overexpression and shRNA knockdown. mTORC1 pathway involvement was tested using rapamycin. Statistical analyses included t-tests and ANOVA, with significance set at (<i>p</i> < 0.05). MSCs from chemotherapy-sensitive and resistant AML patients were compared. Adipogenic differentiation was induced and assessed by Oil Red O staining. RNA sequencing, qPCR, and western blotting were used to analyze the expression of FTO, Raptor, and PPARγ. Global m<sup>6</sup>A levels were measured, and co-culture models with AML cell lines (U937, HL-60, THP-1) were established to evaluate chemoresistance. Gain- and loss-of-function experiments for FTO were performed.</p><p><strong>Results: </strong>CR-AML-MSCs exhibited significantly enhanced adipogenic differentiation (<i>p</i> < 0.01) and elevated PPARγ expression. Co-culture with adipocyte-differentiated CR-AML-MSCs markedly increased resistance to daunorubicin and cytarabine in AML cells (<i>p</i> < 0.01). RNA-Seq analysis revealed enrichment of the mTORC1 signaling pathway and upregulation of raptor. Inhibition of mTORC1 with rapamycin suppressed adipogenic differentiation. Total m<sup>6</sup>A levels were reduced in CR-AML-MSCs, whereas FTO expression was increased. Overexpression of FTO further promoted adipogenesis, upregulated raptor and PPARγ, and enhanced chemoresistance, whereas FTO knockdown attenuated these effects.</p><p><strong>Conclusion: </strong>FTO enhances adipogenic differentiation of CR-AML-MSCs through m<sup>6</sup>A demethylation of raptor, leading to mTORC1 pathway activation and subsequent chemoresistance. These findings reveal a novel mechanism underlying AML chemoresistance and suggest potential therapeutic targets.</p>","PeriodicalId":8690,"journal":{"name":"Balkan Medical Journal","volume":" ","pages":""},"PeriodicalIF":3.8000,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Balkan Medical Journal","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.4274/balkanmedj.galenos.2025.2025-7-150","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"MEDICINE, GENERAL & INTERNAL","Score":null,"Total":0}
引用次数: 0

Abstract

Background: Chemotherapy resistance and relapse in acute myeloid leukemia (AML) are associated with poor prognosis. Bone marrow mesenchymal stem cells (MSCs) show enhanced adipogenic differentiation in AML, which may contribute to chemoresistance; however, the underlying mechanisms remain incompletely understood.

Aims: To investigate how adipogenic differentiation of MSCs from chemotherapy-resistant AML patients (CR-AML-MSCs) promotes chemoresistance, focusing on the roles of the fat mass and obesity-associated protein (FTO) and the mTORC1 pathway.

Study design: Experimental study.

Methods: This study compared bone marrow MSCs from chemotherapy-sensitive (CS) and CR AML patients. Adipogenic differentiation was assessed using Oil Red O staining. RNA sequencing, qPCR, and western blotting were employed to analyze expression of FTO, Raptor, and PPARγ. Global m6A levels were measured, and co-culture models with AML cell lines (U937, HL-60, THP-1) were established to evaluate chemoresistance. Gain- and loss-of-function experiments for FTO were performed using lentiviral overexpression and shRNA knockdown. mTORC1 pathway involvement was tested using rapamycin. Statistical analyses included t-tests and ANOVA, with significance set at (p < 0.05). MSCs from chemotherapy-sensitive and resistant AML patients were compared. Adipogenic differentiation was induced and assessed by Oil Red O staining. RNA sequencing, qPCR, and western blotting were used to analyze the expression of FTO, Raptor, and PPARγ. Global m6A levels were measured, and co-culture models with AML cell lines (U937, HL-60, THP-1) were established to evaluate chemoresistance. Gain- and loss-of-function experiments for FTO were performed.

Results: CR-AML-MSCs exhibited significantly enhanced adipogenic differentiation (p < 0.01) and elevated PPARγ expression. Co-culture with adipocyte-differentiated CR-AML-MSCs markedly increased resistance to daunorubicin and cytarabine in AML cells (p < 0.01). RNA-Seq analysis revealed enrichment of the mTORC1 signaling pathway and upregulation of raptor. Inhibition of mTORC1 with rapamycin suppressed adipogenic differentiation. Total m6A levels were reduced in CR-AML-MSCs, whereas FTO expression was increased. Overexpression of FTO further promoted adipogenesis, upregulated raptor and PPARγ, and enhanced chemoresistance, whereas FTO knockdown attenuated these effects.

Conclusion: FTO enhances adipogenic differentiation of CR-AML-MSCs through m6A demethylation of raptor, leading to mTORC1 pathway activation and subsequent chemoresistance. These findings reveal a novel mechanism underlying AML chemoresistance and suggest potential therapeutic targets.

脂肪量和肥胖相关蛋白介导的骨髓间充质干细胞成脂分化促进急性髓系白血病化疗耐药
背景:急性髓性白血病(AML)的化疗耐药和复发与不良预后相关。骨髓间充质干细胞(MSCs)在AML中表现出增强的脂肪分化,这可能有助于化疗耐药;然而,潜在的机制仍然不完全清楚。目的:研究化疗耐药AML患者骨髓间质干细胞(CR-AML-MSCs)的成脂分化如何促进化疗耐药,重点关注脂肪质量和肥胖相关蛋白(FTO)和mTORC1通路的作用。研究设计:实验研究。方法:本研究比较了化疗敏感(CS)和CR AML患者的骨髓间充质干细胞。油红O染色评估成脂分化。采用RNA测序、qPCR和western blotting分析FTO、Raptor和PPARγ的表达。测量全球m6A水平,并与AML细胞系(U937, HL-60, THP-1)建立共培养模型以评估化疗耐药性。利用慢病毒过表达和shRNA敲低进行FTO的功能获得和功能丧失实验。使用雷帕霉素检测mTORC1通路的参与情况。统计学分析采用t检验和方差分析,显著性设置为(p < 0.05)。比较化疗敏感和耐药AML患者的间充质干细胞。诱导成脂分化,油红O染色评价。采用RNA测序、qPCR和western blotting分析FTO、Raptor和PPARγ的表达。测量全球m6A水平,并与AML细胞系(U937, HL-60, THP-1)建立共培养模型以评估化疗耐药性。进行了FTO的增益和函数损失实验。结果:CR-AML-MSCs成脂分化明显增强(p < 0.01), PPARγ表达升高。与脂肪细胞分化的CR-AML-MSCs共培养可显著提高AML细胞对柔红霉素和阿糖胞苷的耐药性(p < 0.01)。RNA-Seq分析显示mTORC1信号通路的富集和raptor的上调。雷帕霉素抑制mTORC1可抑制脂肪生成分化。总m6A水平在CR-AML-MSCs中降低,而FTO表达增加。过表达FTO进一步促进脂肪形成,上调raptor和PPARγ,并增强化学耐药,而FTO敲低则减弱这些作用。结论:FTO通过raptor的m6A去甲基化,促进CR-AML-MSCs的成脂分化,导致mTORC1通路激活和随后的化疗耐药。这些发现揭示了AML化疗耐药的新机制,并提出了潜在的治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
Balkan Medical Journal
Balkan Medical Journal MEDICINE, GENERAL & INTERNAL-
CiteScore
4.10
自引率
6.70%
发文量
76
审稿时长
6-12 weeks
期刊介绍: The Balkan Medical Journal (Balkan Med J) is a peer-reviewed open-access international journal that publishes interesting clinical and experimental research conducted in all fields of medicine, interesting case reports and clinical images, invited reviews, editorials, letters, comments and letters to the Editor including reports on publication and research ethics. The journal is the official scientific publication of the Trakya University Faculty of Medicine, Edirne, Turkey and is printed six times a year, in January, March, May, July, September and November. The language of the journal is English. The journal is based on independent and unbiased double-blinded peer-reviewed principles. Only unpublished papers that are not under review for publication elsewhere can be submitted. Balkan Medical Journal does not accept multiple submission and duplicate submission even though the previous one was published in a different language. The authors are responsible for the scientific content of the material to be published. The Balkan Medical Journal reserves the right to request any research materials on which the paper is based. The Balkan Medical Journal encourages and enables academicians, researchers, specialists and primary care physicians of Balkan countries to publish their valuable research in all branches of medicine. The primary aim of the journal is to publish original articles with high scientific and ethical quality and serve as a good example of medical publications in the Balkans as well as in the World.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信