Targeting MTHFD2 in acute myeloid leukemia.
Targeting MTHFD2 in acute myeloid leukemia.
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DOI：
10.1084/jem.20151574
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发表时间：
2016-06-27
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影响因子：
--
通讯作者：
Stegmaier K
中科院分区：
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作者：
Pikman Y;Puissant A;Alexe G;Furman A;Chen LM;Frumm SM;Ross L;Fenouille N;Bassil CF;Lewis CA;Ramos A;Gould J;Stone RM;DeAngelo DJ;Galinsky I;Clish CB;Kung AL;Hemann MT;Vander Heiden MG;Banerji V;Stegmaier K
皮克曼等人。证明线粒体酶 MTHFD2 是急性髓系白血病的潜在治疗靶点。针对代谢的药物已成为某些癌症治疗的支柱。我们试图在急性髓系白血病（AML）中寻找新的靶标。一碳叶酸途径，特别是亚甲基四氢叶酸脱氢酶-环水解酶 2 (MTHFD2)，成为我们分析中的首要候选途径。 MTHFD2 是癌症与正常细胞中表达差异最大的代谢酶。敲低 AML 细胞中的 MTHFD2 会降低原发性 AML 母细胞的生长、诱导分化并损害集落形成。在人类异种移植和 MLL-AF9 小鼠白血病模型中，MTHFD2 抑制可减轻白血病负担并延长生存期。根据主要患者 AML 数据和功能基因组筛选，我们确定 FLT3-ITD 是对 MTHFD2 抑制反应的生物标志物。从机制上讲，MYC 调节 MTHFD2 的表达，而 MTHFD2 敲低则抑制 TCA 循环。这项研究支持 MTHFD2 在 AML 中的治疗靶向。
Pikman et al. demonstrate that the mitochondrial enzyme MTHFD2 is a potential therapeutic target in acute myeloid leukemia. Drugs targeting metabolism have formed the backbone of therapy for some cancers. We sought to identify new such targets in acute myeloid leukemia (AML). The one-carbon folate pathway, specifically methylenetetrahydrofolate dehydrogenase-cyclohydrolase 2 (MTHFD2), emerged as a top candidate in our analyses. MTHFD2 is the most differentially expressed metabolic enzyme in cancer versus normal cells. Knockdown of MTHFD2 in AML cells decreased growth, induced differentiation, and impaired colony formation in primary AML blasts. In human xenograft and MLL-AF9 mouse leukemia models, MTHFD2 suppression decreased leukemia burden and prolonged survival. Based upon primary patient AML data and functional genomic screening, we determined that FLT3-ITD is a biomarker of response to MTHFD2 suppression. Mechanistically, MYC regulates the expression of MTHFD2, and MTHFD2 knockdown suppresses the TCA cycle. This study supports the therapeutic targeting of MTHFD2 in AML.