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Haematologica 2019 Volume 104(1):102-112
Acute Myeloid Leukemia
2-Bromopalmitate targets retinoic acid receptor alpha and overcomes all-trans retinoic acid resistance of acute promyelocytic leukemia
Ying Lu,1 Jin-Song Yan,2 Li Xia,1 Kang Qin,1 Qian-Qian Yin,3 Hong-Tao Xu,3 Meng-Qing Gao,2 Xiao-Ning Qu,2 Yu-Ting Sun2 and Guo-Qiang Chen1
YL, JSY and LX contributed equally to this work.
ABSTRACT
Fatty acid oxidation dependency of leukemia cells has been docu- mented in recent studies. Pharmacologic inhibition of fatty acid oxi- dation, 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 degra- dation, 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.
Introduction
It is increasingly recognized that fatty acid oxidation (FAO) plays an important role in supporting cell growth of many cancers including leukemia.1,2 Accordingly, inhibition of FAO by chemical compounds has yielded remarkable effects in sup- pressing cell growth, inducing apoptosis and relieving chemo-resistance, and thus holds therapeutic potential for leukemia.3-6 2-Bromopalmitate (2BP), a palmitate analogue, was initially identified as an inhibitor of FAO around 50 years ago.7,8 Mechanistically, 2BP inhibits carnitine palmitoyltransferase-1(CPT1) and suppress- es the transfer of fatty acyl into mitochondria for oxidation. 7 Over the past decade, 2BP has often been referenced as being a general inhibitor of protein palmitoylation through covalent binding to protein acyl transferases (PAT).9,10 More recently, 2BP was demonstrated to modulate differentiation of neural stem cell and osteoblast
1Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine (SJTU-SM); 2Department of Hematology, Dalian Key Laboratory of Hematology, Liaoning Medical Center for Hematopoietic Stem Cell Transplantation, the Second Hospital of Dalian Medical University and 3Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, China
Correspondence:
stove@shsmu.edu.cn or chengq@shsmu.edu.cn
Received: February 25, 2018. Accepted: July 30, 2018. Pre-published: August 3, 2018.
doi:10.3324/haematol.2018.191916
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