Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine (SJTU-SM)
Department of Hematology, Dalian Key Laboratory of Hematology, Liaoning Medical Center for Hematopoietic Stem Cell Transplantation, the Second Hospital of Dalian Medical University.
Haematologica. 2019 Jan;104(1):102-112. doi: 10.3324/haematol.2018.191916. Epub 2018 Aug 3.
Fatty acid oxidation dependency of leukemia cells has been documented in recent studies. Pharmacologic inhibition of fatty acid oxidation, thereby, displays significant effects in suppressing leukemia. 2-Bromopalmitate, a palmitate analogue, was initially identified as an inhibitor of fatty acid oxidation, and recently recognized as an inhibitor of protein palmitoylation. However, the effects of 2-Bromopalmitate on leukemia and its cellular targets remain obscure. Herein, we discover in cultured cell lines, a transplantable mouse model, and primary blasts that 2-Bromopalmitate presents synergistic differentiation induction with all-trans retinoic acid in acute promyelocytic leukemia. Moreover, 2-Bromopalmitate overcomes all-trans retinoic acid resistance in all-trans retinoic acid-resistant cells and leukemic mice. Mechanistically, 2-Bromopalmitate covalently binds at cysteine 105 and cysteine 174 of retinoic acid receptor alpha (RARα) and stabilizes RARα protein in the presence of all-trans retinoic acid which is known to induce RARα degradation, leading to enhanced transcription of RARα-target genes. Mutation of both cysteines largely abrogates the synergistic effect of 2-Bromopalmitate on all-trans retinoic acid-induced differentiation, demonstrating that 2-Bromopalmitate promotes all-trans retinoic acid-induced differentiation through binding RARα. All-trans retinoic acid-based regimens including arsenic trioxide or chemotherapy, as preferred therapy for acute promyelocytic leukemia, induce adverse events and irreversible resistance. We expect that combining all-trans retinoic acid with 2-Bromopalmitate would be a promising therapeutic strategy for acute promyelocytic leukemia, especially for overcoming all-trans retinoic acid resistance of relapsed acute promyelocytic leukemia patients.
脂肪酸氧化依赖性的白血病细胞已被证明在最近的研究中。药物抑制脂肪酸氧化，因此，显示在抑制白血病的显著效果。 2-溴棕榈酸，棕榈酸类似物，最初被确定为脂肪酸氧化抑制剂，并最近被确认为蛋白质棕榈酰化抑制剂。然而，2-溴棕榈酸对白血病及其细胞靶点的影响仍然不清楚。在此，我们发现，在培养细胞系，可移植的小鼠模型和原始细胞中，2-溴棕榈酸与全反式维甲酸在急性早幼粒细胞白血病中具有协同诱导分化作用。此外，2-溴棕榈酸克服了全反式维甲酸在全反式维甲酸耐药细胞和白血病小鼠中的耐药性。从机制上讲，2-溴棕榈酸与维甲酸受体α（RARα）的半胱氨酸 105 和半胱氨酸 174 共价结合，并在全反式维甲酸存在下稳定 RARα 蛋白，已知全反式维甲酸诱导 RARα 降解，导致 RARα 靶基因的转录增强。这两个半胱氨酸的突变大大削弱了 2-溴棕榈酸对全反式维甲酸诱导分化的协同作用，表明 2-溴棕榈酸通过结合 RARα促进全反式维甲酸诱导的分化。基于全反式维甲酸的方案，包括三氧化二砷或化疗，作为急性早幼粒细胞白血病的首选治疗方法，会引起不良反应和不可逆转的耐药性。我们期望将全反式维甲酸与 2-溴棕榈酸联合使用将是治疗急性早幼粒细胞白血病的一种很有前途的治疗策略，特别是对于克服复发的急性早幼粒细胞白血病患者对全反式维甲酸的耐药性。
