The Folate Cycle Enzyme MTHFR Is a Critical Regulator of Cell Response to MYC-Targeting Therapies.
The Folate Cycle Enzyme MTHFR Is a Critical Regulator of Cell Response to MYC-Targeting Therapies.
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DOI：
10.1158/2159-8290.cd-19-0970
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发表时间：
2020-12
期刊：
影响因子：
28.2
通讯作者：
Puissant A
中科院分区：
文献类型：
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作者：
Su A;Ling F;Vaganay C;Sodaro G;Benaksas C;Dal Bello R;Forget A;Pardieu B;Lin KH;Rutter JC;Bassil CF;Fortin G;Pasanisi J;Antony-Debré I;Alexe G;Benoist JF;Pruvost A;Pikman Y;Qi J;Schlageter MH;Micol JB;Roti G;Cluzeau T;Dombret H;Preudhomme C;Fenouille N;Benajiba L;Golan HM;Stegmaier K;Lobry C;Wood KC;Itzykson R;Puissant A
破译代谢干预对抗癌治疗反应的影响可能会阐明一条改善临床反应的途径。在这里，我们确定了与叶酸循环相关的氨基酸通路，这些通路的激活预测了急性髓系白血病(AML)MYC靶向治疗的敏感性。我们发现，叶酸限制和限速叶酸循环酶MTHFR的缺乏-在大约10%的高加索人中表现出功能降低的多态-在AML的细胞系、原发患者样本和同基因小鼠模型中通过BET和CDK7抑制剂诱导对MYC靶向的耐药性。此外，这种作用通过补充MTHFR酶产物CH3-THF而被消除。从机制上讲，叶酸循环障碍减少了H3K27/K9组蛋白甲基化，并激活了SPI1转录程序，抵消了BET抑制的效果。我们的数据为筛选MTHFR基因多态性和叶酸循环状态以提名最有可能受益于MYC靶向治疗的患者提供了理论基础。
Deciphering the impact of metabolic intervention on response to anticancer therapy may elucidate a path toward improved clinical responses. Here, we identify amino acid-related pathways connected to the folate cycle whose activation predicts sensitivity to MYC-targeting therapies in acute myeloid leukemia (AML). We establish that folate restriction and deficiency of the rate-limiting folate cycle enzyme, MTHFR ― which exhibits reduced-function polymorphisms in about 10% of Caucasians ― induce resistance to MYC targeting by BET and CDK7 inhibitors in cell lines, primary patient samples, and syngeneic mouse models of AML. Further, this effect is abrogated by supplementation with the MTHFR enzymatic product, CH3-THF. Mechanistically, folate cycle disturbance reduces H3K27/K9 histone methylation and activates a SPI1 transcriptional program counteracting the effect of BET inhibition. Our data provide a rationale for screening MTHFR polymorphisms and the folate cycle status to nominate patients most likely to benefit from MYC-targeting therapies.