Mao Shihui, Ling Qing, Pan Jiajia, Li Fenglin, Huang Shujuan, Ye Wenle, Wei Wenwen, Lin Xiangjie, Qian Yu, Wang Yungui, Huang Xin, Huang Jiansong, Wang Jinghan, Jin Jie
Department of Hematology, The First Affiliated Hospital, Zhejiang University College of Medicine, No. 79 Qingchun Road, Hangzhou, Zhejiang, People's Republic of China.
Institute of Hematology, Zhejiang University, Hangzhou, People's Republic of China.
J Transl Med. 2021 Apr 29;19(1):181. doi: 10.1186/s12967-021-02848-9.
Fatty acid oxidation (FAO) provides an important source of energy to promote the growth of leukemia cells. Carnitine palmitoyltransferase 1a(CPT1a), a rate-limiting enzyme of the essential step of FAO, can facilitate cancer metabolic adaptation. Previous reports demonstrated that CPT1a acts as a potential molecular target in solid tumors and hematologic disease. However, no systematic study was conducted to explore the prognostic value of CPT1a expression and possible treatment strategies with CPT1a inhibitor on acute myeloid leukemia (AML).
The expression of CPT1a in 325 cytogenetically normal AML (CN-AML) patients was evaluated using RT-PCR. The combination effects of ST1326 and ABT199 were studied in AML cells and primary patients. MTS was used to measure the cell proliferation rate. Annexin V/propidium iodide staining and flow cytometry analysis was used to measure the apoptosis rate. Western blot was used to measure the expression of Mcl-1. RNAseq and GC-TOFMS were used for genomic and metabolic analysis.
In this study, we found AML patients with high CPT1a expression (n = 245) had a relatively short overall survival (P = 0.01) compared to patients in low expression group (n = 80). In parallel, downregulation of CPT1a inhibits proliferation of AML cells. We also conducted genomic and metabolic interactive analysis in AML patients, and found several essential genes and pathways related to aberrant expression of CPT1a. Moreover, we found downregulation of CPT1a sentitized BCL-2 inhibitor ABT199 and CPT1a-selective inhibitor ST1326 combined with ABT199 had a strong synergistic effect to induce apoptosis in AML cells and primary patient blasts for the first time. The underlying synergistic mechanism might be that ST1326 inhibits pGSK3β and pERK expression, leading to downregulation of Mcl-1.
Our study indicates that overexpression of CPT1a predicts poor clinical outcome in AML. CPT1a-selective inhibitor ST1326 combined with Bcl-2 inhibitor ABT199 showed strong synergistic inhibitory effects on AML.
脂肪酸氧化（FAO）为白血病细胞的生长提供了重要的能量来源。肉碱棕榈酰转移酶1a（CPT1a）是FAO关键步骤的限速酶，可促进癌症代谢适应。既往报道表明CPT1a是实体瘤和血液系统疾病潜在的分子靶点。然而，尚未开展系统研究来探索CPT1a表达的预后价值以及使用CPT1a抑制剂治疗急性髓系白血病（AML）的可能策略。
采用逆转录-聚合酶链反应（RT-PCR）评估325例细胞遗传学正常的AML（CN-AML）患者中CPT1a的表达。在AML细胞和原发性患者中研究ST1326和ABT199的联合作用。采用甲基噻唑基四唑（MTS）法检测细胞增殖率。采用膜联蛋白V/碘化丙啶染色和流式细胞术分析检测凋亡率。采用蛋白质免疫印迹法检测髓细胞白血病-1（Mcl-1）的表达。采用RNA测序（RNAseq）和气相色谱-飞行时间质谱（GC-TOFMS）进行基因组和代谢分析。
在本研究中，我们发现与低表达组（n = 80）患者相比，CPT1a高表达的AML患者（n = 245）总生存期相对较短（P = 0.01）。同时，CPT1a的下调抑制AML细胞的增殖。我们还对AML患者进行了基因组和代谢交互分析，发现了几个与CPT1a异常表达相关的关键基因和通路。此外，我们首次发现CPT1a的下调使BCL-2抑制剂ABT199增敏，并且CPT1a选择性抑制剂ST1326与ABT199联合使用对AML细胞和原发性患者原始细胞诱导凋亡具有强烈的协同作用。潜在的协同机制可能是ST1326抑制磷酸化糖原合成酶激酶3β（pGSK3β）和磷酸化细胞外信号调节激酶（pERK）的表达，导致Mcl-1下调。
我们的研究表明CPT1a的过表达预示AML患者临床预后不良。CPT1a选择性抑制剂ST1326与Bcl-2抑制剂ABT199联合使用对AML显示出强烈的协同抑制作用。
