Abstract
BackgroundFatty 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).MethodsThe 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.ResultsIn 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.ConclusionOur 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.
Highlights
Fatty acid oxidation (FAO) provides an important source of energy to promote the growth of leukemia cells
In the multivariable analysis, high carnitine palmitoyl transferase1a (CPT1a) expression is associated with poor overall survival (OS) [HR, 1.674 (1.097, 2.557); P = 0.017, Table 2] after adjusting age, WBC, ENL classification, DMNT3a and IDH1, IDH2 mutations
The results showed that high expression levels of CPT1a were detected in THP-1, Fig.1 a qRT-PCR analysis of CPT1a mRNA expressionin normal cells (n = 8) and CN-acute myeloid leukemia (AML) samples (n = 325) (t-test). b Kaplan–Meier analysis of overall survival (OS) according to CPT1a mRNA expression in primary blasts from 325 AML patients. c Kaplan–Meier analysis of event free survival (EFS) according to CPT1a mRNA expression in primary blasts from 325 AML patients. d qPCR and Western blotting analysis of CPT1a expression in human AML cell lines. e Western blotting analysis of the CPT1a protein level in THP-1 and HL-60 cells transduced with 2 different CPT1a shRNAs
Summary
Fatty acid oxidation (FAO) provides an important source of energy to promote the growth of leukemia cells. Targeting CPT1a has shown remarkable anti-leukemia activity: A novel CPT1a inhibitor ST1326 has been proved effective on leukemia cell lines and primary cells obtained from patients with hematologic malignancies [8]. There is not yet a study to exclusively evaluate the prognostic value of CPT1a expression and possible combinational strategy with CPT1a inhibitor on AML.A majority of leukemia cells have a survival advantage over normal cells because they fail to undergo apoptosis [9]. Compared to other drugs in its class, venetoclax has lower hematological toxicity [11] To date, it has been approved for the treatment of first-line and relapsed/refractory chronic lymphocytic leukemia (CLL) and AML [12]. Previous study show that ABT199 (Venetoclax) has promising antileukaemic activity in AML therapy but increasing Mcl-1 limits its effect [15]
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