SMYD3 Activates Fatty Acid β-oxidation to Promote Self-Renewal of Leukemia Stem Cells

IF 12.5 1区医学 Q1 ONCOLOGY

Cancer research Pub Date : 2025-03-13 DOI:10.1158/0008-5472.can-24-2117

Min Zhou, Zihao Wu, Fen Wei, Chen Duan, Xiaoying Lin, Waiyi Zou, Chang Liu, Jingxuan Pan, Yanli Jin

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引用次数: 0

Abstract

The development of BCR-ABL tyrosine kinase inhibitors (TKIs) has revolutionized disease management of chronic myeloid leukemia (CML). However, the persistence of leukemia stem cells (LSCs) remains a major barrier to curing CML, highlighting the urgent need to identify the regulators supporting LSCs. In this study, we validated the critical role of the histone methyltransferase SET and MYND domain containing 3 (SMYD3) in the maintenance of LSCs in CML. SMYD3 was overexpressed in CML LSCs and enhanced the survival and self-renewal properties of human primary CD34+ CML cells. Loss of SMYD3 blocked leukemogenesis and impaired the self-renewal and disease reconstitution abilities of LSCs in mice without affecting normal hematopoiesis. SMYD3 stimulated fatty acid β-oxidation (FAO) in LSCs by activating the FABP5/PPARD/CPT1A signaling axis in a methyltransferase activity-dependent manner. Blocking CPT1A-mediated FAO reduced the function of human CML LSCs in vitro and depleted LSCs in vivo. These findings shed light on the role of histone lysine methylation-mediated FAO in the maintenance of LSCs and suggest that SMYD3 may serve as a therapeutic target for treating patients with CML.

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SMYD3激活脂肪酸β-氧化促进白血病干细胞自我更新

BCR-ABL酪氨酸激酶抑制剂（TKIs）的开发已经彻底改变了慢性髓性白血病（CML）的疾病管理。然而，白血病干细胞（LSCs）的持续存在仍然是治疗CML的主要障碍，因此迫切需要确定支持LSCs的调节因子。在这项研究中，我们验证了组蛋白甲基转移酶SET和含有3的MYND结构域（SMYD3）在CML中维持LSCs的关键作用。SMYD3在CML LSCs中过表达，增强了人原代CD34+ CML细胞的存活和自我更新特性。SMYD3的缺失阻断了白血病的发生，损害了小鼠LSCs的自我更新和疾病重建能力，但不影响正常的造血功能。SMYD3以甲基转移酶活性依赖的方式激活FABP5/PPARD/CPT1A信号轴，刺激LSCs中的脂肪酸β-氧化（FAO）。阻断cpt1a介导的FAO在体外降低了人CML LSCs的功能，并在体内耗尽了LSCs。这些发现揭示了组蛋白赖氨酸甲基化介导的FAO在LSCs维持中的作用，并表明SMYD3可能作为治疗CML患者的治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer research 医学-肿瘤学

CiteScore

16.10

自引率

0.90%

发文量

7677

审稿时长

2.5 months

期刊介绍： Cancer Research, published by the American Association for Cancer Research (AACR), is a journal that focuses on impactful original studies, reviews, and opinion pieces relevant to the broad cancer research community. Manuscripts that present conceptual or technological advances leading to insights into cancer biology are particularly sought after. The journal also places emphasis on convergence science, which involves bridging multiple distinct areas of cancer research. With primary subsections including Cancer Biology, Cancer Immunology, Cancer Metabolism and Molecular Mechanisms, Translational Cancer Biology, Cancer Landscapes, and Convergence Science, Cancer Research has a comprehensive scope. It is published twice a month and has one volume per year, with a print ISSN of 0008-5472 and an online ISSN of 1538-7445. Cancer Research is abstracted and/or indexed in various databases and platforms, including BIOSIS Previews (R) Database, MEDLINE, Current Contents/Life Sciences, Current Contents/Clinical Medicine, Science Citation Index, Scopus, and Web of Science.