Abstract 3749: Multi-Omic Characterization of Treatment-Naive Acute Myeloid Leukemia Reveals Subtype-Specific Features and Biomarkers of Drug Response

Abstract Acute myeloid leukemia (AML) is a heterogeneous cancer of the blood and bone marrow with poor prognosis. To elucidate the underlying mechanisms that drive AML as part of the Clinical Proteomic Tumor Analysis Consortium (CPTAC) effort, we performed comprehensive genomics, transcriptomics, proteomics including multiple post-translational modifications (PTMs), metabolomics, and lipidomics characterization of 173 treatment-naïve AML patients. By applying similarity network fusion using collected transcriptomics and proteomics data jointly, we identified 8 proteogenomic subtypes. These subtypes not only harbored recurrent genomic aberrations of AML similar to the current clinical classification but also unveiled new subtype-specific phenotypes. Utilizing previously published single-cell RNAseq data as reference, we also demonstrated that these subtypes are also enriched for cellular hierarchies including primitive AML, CD14+ monocyte-like, and GMP-like AML. Interestingly, proteogenomic subtyping revealed a distinct NPM1-mutant subset of AMLs characterized by outlier transcription factor expression and activities of FOXC1 and POU2F1. Further, we derived a shared primitive signature across NPM1 mutated AML and myelodysplastic syndrome related AML that could be beneficial to determine drug response. Among the proposed primitive signatures, we found a protein marker MAP1A was able to predict response of venetoclax and NF-kB activation inhibitor across NPM1 mutated AML and myelodysplastic syndrome related AML. To translate these proteogenomics subtypes into potential clinical applications, we further employed methods to evaluate drug responses of proteogenomics subtypes by integrating CPTAC cohort with the previously published Beat AML cohort, which focuses on ex-vivo drug testing, and revealed subtype-specific drug responses. Together with findings in subtypes with PTM and metabolism aberrations, our study provided new valuable insights and clinical relevance of these newly identified in AML. Citation Format: Yi Hsiao, Alec Chu, Yamei Deng, Chenwei Wang, Jennifer Kyle, Yongchao Dou, Jame Pino, Camilo Posso, Leanne Henry, Lijun Chen, Ginny Xiaohe Li, Mamie Lih, Yifat Geffen, Fengchao Yu, Li Ding, Gilbert S. Omenn, Chandan Kumar, Saravana M. Dhanasekaran, Elie Traer, Jefferey W. Tyner, Hui Zhang, Tao Liu, Sara S. Gosline, Bing Zhang, Arul M. Chinnaiyan, Alexey I. Nesvizhskii, Marcin Cieslik, The CPTAC Consortium. Multi-Omic Characterization of Treatment-Naive Acute Myeloid Leukemia Reveals Subtype-Specific Features and Biomarkers of Drug Response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3749.