<br>TGFB1在急性髓系白血病化疗耐药中的作用及机制,Cellular Signalling

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TGFB1在急性髓系白血病化疗耐药中的作用及机制
Cellular Signalling ( IF 4.4 ) Pub Date : 2024-01-01 , DOI: 10.1016/j.cellsig.2023.111027
Xue Liang ₁ , Ji Zhou ₂ , Cong Li ₁ , Huiping Wang ₁ , Yang Wan ₁ , Chun Ling ₁ , Lianfang Pu ₁ , Wanqiu Zhang ₁ , Mengmeng Fan ₁ , Jingfang Hong ₂ , Zhimin Zhai ₁

Affiliation

复发或难治性（R/R）急性髓系白血病（AML）患者通常预后很差，耐药性是主要限制因素之一。在本研究中，我们旨在探讨转化生长因子-β1（TGFB1）在 AML 耐药中的作用。首先，与初诊患者相比，R/R患者血清和骨髓中TGFB1水平较高，根据骨髓活检的免疫组化结果，这种现象可能是由于分泌的TGFB1来源不同所致。同样，AML耐药细胞系中TGFB1的表达高于其亲本细胞系，通过特异性抑制剂阻断TGFB信号通路可降低对化疗药物的耐药性。另一方面，外源性TGFB1还可促进AML亲代细胞衰老和化疗耐药。接下来，我们发现耐药细胞中SOX4水平上调，并且用外源TGFB1处理的亲本细胞诱导SOX4水平上调。 siRNA 对 SOX4 表达的干扰降低了 TGFB1 诱导的对化疗药物的敏感性。最后，我们进行代谢组学分析，发现抑制TGFB信号通路或干扰SOX4表达后丙氨酸、天冬氨酸和谷氨酸代谢途径以及甘油磷脂代谢途径降低。本研究得出的结论是，R/R AML 患者和耐药菌株中的 TGFB1 水平显着升高。阻断TGFB信号通路可以通过抑制SOX4表达和代谢重编程来增强耐药细胞的化疗敏感性。

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The roles and mechanisms of TGFB1 in acute myeloid leukemia chemoresistance

Relapsed or Refractory (R/R) Acute Myeloid Leukemia (AML) patients usually have very poor prognoses, and drug-resistance is one of the major limiting factors. In this study, we aimed to explore the functions of Transforming Growth Factor-β1 (TGFB1) in AML drug-resistance. First, TGFB1 levels in serum and bone marrow are higher in R/R patients compared with newly diagnosed patients, this phenomenon could be due to different sources of secreted TGFB1 according to immunohistochemistry of marrow biopsies. Similarly, TGFB1 expression in AML drug-resistant cell lines is higher than that in their parental cell lines, and blocking the TGFB signaling pathway by specific inhibitors decreased resistance to chemotherapeutic agents. On the other hand, exogenous TGFB1 can also promote AML parental cells senescence and chemotherapy resistance. Next, we found SOX4 level is upregulated in drug-resistant cells, and parental cells treated with exogenous TGFB1 induced upregulation of SOX4 levels. Interference of SOX4 expression by siRNA diminished the TGFB1-induced sensitivity to chemotherapeutic agents. Finally, we conduct metabolomic analysis and find Alanine, aspartate and glutamate metabolism pathway, and Glycerophospholipid metabolism pathway are decreased after inhibiting TGFB signaling pathway or interfering SOX4 expression. This study concludes that TGFB1 level in R/R AML patients and drug-resistant strains is significantly increased. Blocking the TGFB signaling pathway can enhance the chemosensitivity of drug-resistant cells by suppressing SOX4 expression and metabolic reprogramming.

更新日期：2024-01-01

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