RSL3 通过 MYB/Bcl-2 信号通路增强骨髓增生异常综合征细胞中 ROS 介导的细胞凋亡。

RSL3 enhances ROS-mediated cell apoptosis of myelodysplastic syndrome cells through MYB/Bcl-2 signaling pathway.

机构信息

Department of Clinical Laboratory, The Affiliated Nanhua Hospital, University of South China, Hengyang, 421001, Hunan, China.

Molecular Biology Research Center & Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, 410078, Hunan, China.

出版信息

Cell Death Dis. 2024 Jul 2;15(7):465. doi: 10.1038/s41419-024-06866-5.

DOI:10.1038/s41419-024-06866-5

PMID:38956026

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11219730/

Abstract

Myelodysplastic syndromes (MDS) are clonal hematopoietic malignancies and seriously threaten people's health. Current therapies include bone marrow transplantation and several hypomethylating agents. However, many elderly patients cannot benefit from bone marrow transplantation and many patients develop drug resistance to hypomethylating agents, making it urgent to explore novel therapy. RSL3 can effectively induce ferroptosis in various tumors and combination of RSL3 and hypomethylating agents is promising to treat many tumors. However, its effect in MDS was unknown. In this study, we found that RSL3 inhibited MDS cell proliferation through inducing ROS-dependent apoptosis. RSL3 inhibited Bcl-2 expression and increased caspase 3 and PARP cleavage. RNA-seq analysis revealed that MYB may be a potential target of RSL3. Rescue experiments showed that overexpression of MYB can rescue MDS cell proliferation inhibition caused by RSL3. Cellular thermal shift assay showed that RSL3 binds to MYB to exert its function. Furthermore, RSL3 inhibited tumor growth and decreased MYB and Bcl-2 expression in vivo. More importantly, RSL3 decreased the viability of bone marrow mononuclear cells (BMMCs) isolated from MDS patients, and RSL3 had a synergistic effect with DAC in MDS cells. Our studies have uncovered RSL3 as a promising compound and MYB/Bcl-2 signaling pathway as a potential target for MDS treatment.

摘要

骨髓增生异常综合征（MDS）是一种克隆性造血恶性肿瘤，严重威胁着人们的健康。目前的治疗方法包括骨髓移植和几种低甲基化剂。然而，许多老年患者不能从骨髓移植中获益，许多患者对低甲基化剂产生耐药性，因此迫切需要探索新的治疗方法。RSL3 可以有效地诱导多种肿瘤中的铁死亡，RSL3 与低甲基化剂的联合治疗有希望治疗许多肿瘤。然而，其在 MDS 中的作用尚不清楚。在本研究中，我们发现 RSL3 通过诱导 ROS 依赖性细胞凋亡抑制 MDS 细胞增殖。RSL3 抑制 Bcl-2 的表达，增加 caspase 3 和 PARP 的切割。RNA-seq 分析表明，MYB 可能是 RSL3 的潜在靶点。挽救实验表明，过表达 MYB 可以挽救 RSL3 引起的 MDS 细胞增殖抑制。细胞热转移分析表明，RSL3 通过与 MYB 结合发挥其功能。此外，RSL3 抑制体内肿瘤生长并降低 MYB 和 Bcl-2 的表达。更重要的是，RSL3 降低了 MDS 患者骨髓单个核细胞（BMMCs）的活力，并且 RSL3 与 DAC 在 MDS 细胞中具有协同作用。我们的研究揭示了 RSL3 作为一种有前途的化合物，以及 MYB/Bcl-2 信号通路作为 MDS 治疗的潜在靶点。