Shih-Chun A. Chu, Yi Hsiao, Chenwei Wang, Jennifer E. Kyle, Raghav Jain, Yamei Deng, Marina Gritsenko, Leanne E. Henry, Jonathan T. Lei, Yongchao Dou, Bahar Tercan, Zhiao Shi, Mahnoor Gondal, Chia‐Feng Tsai, John M. Elizarraras, Rosalie Chu, Fengchao Yu, Sunil K. Joshi, Xiaojun Jing, Daniel A. Polasky, Karl Weitz, Ginny Xiaohe Li, Vanessa Paurus, Chaevien Clendinen, Athena Schepmoes, Priscila M. Lalli, Josie Eder, Javier E. Flores, Kelly G. Stratton, James C. Pino, Camilo Posso, Vladislav Petyuk, Tyler J. Sagendorf, Yuanwei Xu, Omar M. Ibrahim, Ronald Moore, Rui Zhao, Jin Chen, Matthew Monroe, Mathangi Thiagarajan, Galen Hostetter, Chelsea Newton, Eunkyung An, Ana I. Robles, Xi Zhang, Nathan J. Edwards, Lu Yin, Hui Zhang, Haitham Abdelhakim, Paul Piehowski, Mehdi Mesri, Richard D. Smith, Chandan Kumar‐Sinha, Cristina E. Tognon, Jennifer Dunlap, Elie Traer, Li Ding, Jeffrey Tyner, Arul M. Chinnaiyan, Gilbert S. Omenn, KD Rodland, Saravana M. Dhanasekaran, Sara JC Gosline, Alexey I. Nesvizhskii, Bing Zhang, Tao Liu, Marcin Cieślik, Shelby Abts, Anupriya Agarwal, Veera Baladandayuthapani, Anand Basu, Garana Belinda, William Bocik, Melissa Borucki, Shuang Cai, Stancioaica Maria Camelia, Steven Carr, Patricia Castro, Daniel Chan, Hanbyul Cho, Rosalie Chu, Chaevien Clendinen, Simona Colantonio, Reese Crispen, Diwaker Davar, Rajiv Dhir, Marcin Domagalski, John Evangelista, Brenda Fevrier-Sullivan, Rafael Fonseca, John Freymann, Victoria Fulidou, Sharon Gaheen, Пенчо Георгиев, Gad Getz, Lidia Gil, Michael A. Gillette, Andrew K. Godwin, Charles A. Goldthwaite, Vladislav Golubkov
Acute myeloid leukemia (AML) is a genetically and phenotypically heterogeneous hematological malignancy. Here, to better define this clinically taxing and translationally challenging malignancy, we applied a multiomics approach, consisting of 13 modalities to analyze 173 treatment-naive individuals with AML. By integrating these 'omes', we identified distinct AML subtypes, genotype-phenotype associations, biomarkers and pathobiological mechanisms. Across the spectrum of primitive and committed AML, we found extensive metabolomic and lipidomic reprogramming driven by divergent MYC and mTOR activity. We linked metabolic changes to striking hyperacetylation of mitochondrial proteins in CEBPA-mutant AML. Protein-centric subtyping revealed a distinct NPM1-mutant subset characterized by outlier expression of FOXC1 and HOXB8/9. To nominate therapeutic targets across subtypes, we developed a multiomic machine-learning approach and validated MTA1 as a contributor to panobinostat resistance. Altogether our findings underscore the complex nature of AML and provide a clinically and translationally informed unified view that reveals coalescent phenotypes across multiomic layers.