Fatty acid metabolism underlies venetoclax resistance in acute myeloid leukemia stem cells.
Fatty acid metabolism underlies venetoclax resistance in acute myeloid leukemia stem cells.
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DOI：
10.1038/s43018-020-00126-z
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发表时间：
2020-12
期刊：
影响因子：
22.7
通讯作者：
Jordan CT
中科院分区：
文献类型：
--
作者：
Stevens BM;Jones CL;Pollyea DA;Culp-Hill R;D'Alessandro A;Winters A;Krug A;Abbott D;Goosman M;Pei S;Ye H;Gillen AE;Becker MW;Savona MR;Smith C;Jordan CT
维奈托克联合阿扎胞苷（ven/aza）已成为治疗急性髓性白血病（AML）的一种有前景的方案，在新诊断的患者中临床缓解率较高。然而，大约30%的新诊断患者和大多数复发患者在使用ven/aza后没有达到缓解。我们以前报道过，ven/aza的疗效是基于通过抑制氨基酸代谢的机制根除AML干细胞，这是原始AML细胞驱动氧化磷酸化所需的过程。在本文中，我们证明了对ven/aza的抗性通过上调脂肪酸氧化（FAO）发生，这是由于RAS通路突变或作为复发性疾病的补偿适应而发生的。FAO的使用避免了氨基酸代谢的需要，从而使ven/aza无效。FAO的药理学抑制恢复了耐药AML细胞对ven/aza的敏感性。我们提出抑制FAO作为解决ven/aza抗性的治疗策略。
Venetoclax with azacitidine (ven/aza) has emerged as a promising regimen for acute myeloid leukemia (AML), with a high percentage of clinical remissions in newly diagnosed patients. However, approximately 30% of newly diagnosed and the majority of relapsed patients do not achieve remission with ven/aza. We previously reported that ven/aza efficacy is based on eradication of AML stem cells through a mechanism involving inhibition of amino acid metabolism, a process which is required in primitive AML cells to drive oxidative phosphorylation. Herein we demonstrate that resistance to ven/aza occurs via up-regulation of fatty acid oxidation (FAO), which occurs due to RAS pathway mutations, or as a compensatory adaptation in relapsed disease. Utilization of FAO obviates the need for amino acid metabolism, thereby rendering ven/aza ineffective. Pharmacological inhibition of FAO restores sensitivity to ven/aza in drug resistant AML cells. We propose inhibition of FAO as a therapeutic strategy to address ven/aza resistance.
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影响因子：
50.3
作者：
Jones CL;Stevens BM;D'Alessandro A;Reisz JA;Culp-Hill R;Nemkov T;Pei S;Khan N;Adane B;Ye H;Krug A;Reinhold D;Smith C;DeGregori J;Pollyea DA;Jordan CT
通讯作者：
Jordan CT
影响因子：
23.9
作者：
Lagadinou, Eleni D.;Sach, Alexander;Callahan, Kevin;Rossi, Randall M.;Neering, Sarah J.;Minhajuddin, Mohammad;Ashton, John M.;Pei, Shanshan;Grose, Valerie;O'Dwyer, Kristen M.;Liesveld, Jane L.;Brookes, Paul S.;Becker, Michael W.;Jordan, Craig T.
通讯作者：
Jordan, Craig T.
影响因子：
20.3
作者：
Ho, Tzu-Chieh;LaMere, Mark;Becker, Michael W.
通讯作者：
Becker, Michael W.
DOI：
10.1007/978-1-4939-9236-2_2
发表时间：
2019-01-01
期刊：
HIGH-THROUGHPUT METABOLOMICS: METHODS AND PROTOCOLS
影响因子：
--
作者：
Nemkov, Travis;Reisz, Julie A.;D'Alessandro, Angelo
通讯作者：
D'Alessandro, Angelo
影响因子：
10.1
作者：
Kuusanmaki, Heikki;Leppa, Aino-Maija;Heckman, Caroline A.
通讯作者：
Heckman, Caroline A.