Journal article
Integrated proteogenomic and metabolomic profiling of acute myeloid leukemias to identify molecular subtypes and associated therapy targets
Nature cancer
06/12/2026
DOI: 10.1038/s43018-026-01175-6
PMCID: PMC13309276
PMID: 42286338
Abstract
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.
Details
- Title: Subtitle
- Integrated proteogenomic and metabolomic profiling of acute myeloid leukemias to identify molecular subtypes and associated therapy targets
- Creators
- Shih-Chun A Chu - University of MichiganYi Hsiao - University of MichiganChenwei Wang - Baylor College of MedicineJennifer E Kyle - Pacific Northwest National LaboratoryRaghav Jain - Pacific Northwest National LaboratoryYamei Deng - University of MichiganMarina A Gritsenko - Pacific Northwest National LaboratoryLeanne E Henry - University of MichiganJonathan T Lei - Baylor College of MedicineYongchao Dou - Baylor College of MedicineBahar Tercan - Institute for Systems BiologyZhiao Shi - Baylor College of MedicineMahnoor N Gondal - University of MichiganChia-Feng Tsai - Pacific Northwest National LaboratoryJohn M Elizarraras - Baylor College of MedicineRosalie K Chu - Pacific Northwest National LaboratoryFengchao Yu - University of MichiganSunil K Joshi - Stanford MedicineXiaojun Jing - University of MichiganDaniel A Polasky - University of MichiganKarl K Weitz - Pacific Northwest National LaboratoryGinny Xiaohe Li - University of MichiganVanessa L Paurus - Pacific Northwest National LaboratoryChaevien S Clendinen - Pacific Northwest National LaboratoryAthena A Schepmoes - Pacific Northwest National LaboratoryPriscila M Lalli - Pacific Northwest National LaboratoryJosie G Eder - Pacific Northwest National LaboratoryJavier E Flores - Pacific Northwest National LaboratoryKelly G Stratton - Pacific Northwest National LaboratoryJames C Pino - Pacific Northwest National LaboratoryCamilo Posso - Pacific Northwest National LaboratoryVladislav A Petyuk - Pacific Northwest National LaboratoryTyler J Sagendorf - Pacific Northwest National LaboratoryYuanwei Xu - Johns Hopkins UniversityOmar M Ibrahim - James S. McDonnell FoundationRonald J Moore - Pacific Northwest National LaboratoryRui Zhao - Pacific Northwest National LaboratoryJin Chen - University of MichiganMatthew E Monroe - Pacific Northwest National LaboratoryMathangi Thiagarajan - National Cancer InstituteGalen Hostetter - Van Andel InstituteChelsea Newton - Van Andel InstituteEunkyung An - National Cancer InstituteAna I Robles - National Cancer InstituteXu Zhang - Office of Cancer Clinical Proteomics Research, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, MD, USANathan J Edwards - Georgetown UniversityYin Lu - ICF, Rockville, MD, USAHui Zhang - Johns Hopkins UniversityHaitham Abdelhakim - The University of Kansas Cancer CenterPaul D Piehowski - Pacific Northwest National LaboratoryMehdi Mesri - National Cancer InstituteRichard D Smith - Pacific Northwest National LaboratoryChandan Kumar-Sinha - University of MichiganCristina E Tognon - Oregon Health & Science UniversityJennifer Dunlap - Oregon Health & Science UniversityElie Traer - Oregon Health & Science UniversityLi Ding - Washington University in St. LouisJeffrey W Tyner - Oregon Health & Science UniversityArul M Chinnaiyan - University of MichiganGilbert S Omenn - University of MichiganKarin D Rodland - Pacific Northwest National LaboratorySaravana M Dhanasekaran - University of MichiganSara J C Gosline - Pacific Northwest National LaboratoryAlexey I Nesvizhiskii - University of MichiganBing Zhang - Baylor College of MedicineTao Liu - Pacific Northwest National LaboratoryMarcin P Cieslik - University of MichiganClinical Proteomic Tumor Analysis Consortium
- Resource Type
- Journal article
- Publication Details
- Nature cancer
- DOI
- 10.1038/s43018-026-01175-6
- PMID
- 42286338
- PMCID
- PMC13309276
- NLM abbreviation
- Nat Cancer
- ISSN
- 2662-1347
- eISSN
- 2662-1347
- Publisher
- NATURE PORTFOLIO
- Grant note
- U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)
This work was supported by grants U24CA270823, U24CA271079, U24CA271012, U24CA271075, U24CA271076, U24CA271037, U24CA271114, U01CA271412, U01CA271410, U01CA271407, U01CA271402 and U24CA210955 from the National Cancer Institute's CPTAC. PNNL is a multiprogram national laboratory operated by the Battelle Memorial Institute for the DOE under contract DE-AC05-76RL01830.
- Language
- English
- Electronic publication date
- 06/12/2026
- Academic Unit
- Biostatistics
- Record Identifier
- 9985174807202771
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