Integrated genomic-metabolic classification of acute myeloid leukemia defines a subgroup with NPM1 and cohesin/DNA damage mutations.
Integrated genomic-metabolic classification of acute myeloid leukemia defines a subgroup with NPM1 and cohesin/DNA damage mutations.
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DOI：
10.1038/s41375-021-01318-x
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发表时间：
2021-10
期刊：
影响因子：
11.4
通讯作者：
Martinelli G
中科院分区：
文献类型：
--
作者：
Simonetti G;Mengucci C;Padella A;Fonzi E;Picone G;Delpino C;Nanni J;De Tommaso R;Franchini E;Papayannidis C;Marconi G;Pazzaglia M;Perricone M;Scarpi E;Fontana MC;Bruno S;Tebaldi M;Ferrari A;Bochicchio MT;Ghelli Luserna Di Rorà A;Ghetti M;Napolitano R;Astolfi A;Baldazzi C;Guadagnuolo V;Ottaviani E;Iacobucci I;Cavo M;Castellani G;Haferlach T;Remondini D;Capozzi F;Martinelli G
虽然靶向细胞代谢是急性髓细胞白血病（AML）的一种有前途的治疗策略，但代谢依赖性在很大程度上尚未探索。我们的目的是根据AML患者的代谢状况对其进行分类，并绘制代谢和基因组图谱之间的联系。与单独的生物流体分析相比，血清和尿液代谢组学组合改善了AML表征。在细胞内水平，AML表现为氨基酸、核苷酸、脂质和生物能量代谢失调。细胞内和生物流体代谢组学的整合提供了多胺，嘌呤，酮体和多不饱和脂肪酸和三羧酸循环的代谢变化的地图。细胞内代谢组区分了三个AML簇，与不同的基因组谱相关：NPM 1突变（mut），染色质/剪接体-mut和TP 53-mut/非整倍体AML，这些AML通过生物流体分析得到证实。有趣的是，整合的基因组-代谢谱定义了NPM 1-mut AML的两个亚组。一种是富含粘着蛋白/DNA损伤相关基因（NPM 1/粘着蛋白-mut AML）的突变，并显示血清胆碱+三甲胺-N-氧化物和亮氨酸增加，突变负荷更高，炎症状态降低的转录组学特征以及对EGFR和MET抑制的更好的离体反应。NPM 1/cohesin-mut和NPM 1-mut之间的酶编码基因的转录差异允许对细胞内代谢扰动进行计算机模拟。这种方法预测了NPM 1/cohesin-mut AML中NAD和嘌呤代谢的改变，表明潜在的脆弱性，值得在治疗上进行探索。
Although targeting of cell metabolism is a promising therapeutic strategy in acute myeloid leukemia (AML), metabolic dependencies are largely unexplored. We aimed to classify AML patients based on their metabolic landscape and map connections between metabolic and genomic profiles. Combined serum and urine metabolomics improved AML characterization compared with individual biofluid analysis. At intracellular level, AML displayed dysregulated amino acid, nucleotide, lipid, and bioenergetic metabolism. The integration of intracellular and biofluid metabolomics provided a map of alterations in the metabolism of polyamine, purine, keton bodies and polyunsaturated fatty acids and tricarboxylic acid cycle. The intracellular metabolome distinguished three AML clusters, correlating with distinct genomic profiles: NPM1-mutated(mut), chromatin/spliceosome-mut and TP53-mut/aneuploid AML that were confirmed by biofluid analysis. Interestingly, integrated genomic-metabolic profiles defined two subgroups of NPM1-mut AML. One was enriched for mutations in cohesin/DNA damage-related genes (NPM1/cohesin-mut AML) and showed increased serum choline + trimethylamine-N-oxide and leucine, higher mutation load, transcriptomic signatures of reduced inflammatory status and better ex-vivo response to EGFR and MET inhibition. The transcriptional differences of enzyme-encoding genes between NPM1/cohesin-mut and NPM1-mut allowed in silico modeling of intracellular metabolic perturbations. This approach predicted alterations in NAD and purine metabolism in NPM1/cohesin-mut AML that suggest potential vulnerabilities, worthy of being therapeutically explored.
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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：
11.4
作者：
Ju HQ;Zhan G;Huang A;Sun Y;Wen S;Yang J;Lu WH;Xu RH;Li J;Li Y;Garcia-Manero G;Huang P;Hu Y
通讯作者：
Hu Y
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：
50.3
作者：
Figueroa ME;Abdel-Wahab O;Lu C;Ward PS;Patel J;Shih A;Li Y;Bhagwat N;Vasanthakumar A;Fernandez HF;Tallman MS;Sun Z;Wolniak K;Peeters JK;Liu W;Choe SE;Fantin VR;Paietta E;Löwenberg B;Licht JD;Godley LA;Delwel R;Valk PJ;Thompson CB;Levine RL;Melnick A
通讯作者：
Melnick A
影响因子：
4
作者：
Alseth, Ingrun;Dalhus, Bjorn;Bjoras, Magnar
通讯作者：
Bjoras, Magnar