Abstract 7354: Proteogenomic and metabolomic characterization of acute myeloid leukemia

Abstract Acute myeloid leukemia (AML) is a blood malignancy of poor prognosis with marked heterogeneity. 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 (phosphorylation, acetylation, and glycosylation), metabolomics, and lipidomics characterization of 173 treatment-naïve AML patients. Applying the similarity network fusion method on both transcriptomics and proteomics data, we identified 8 proteogenomic clusters. These clusters recapitulate specific recurrent mutations and established clinical subtypes available within the cohort. We used single-cell RNAseq data as a reference to perform immune component analysis for collected bulk samples. The result reveals that our proteogenomic clustering also captures the variations of AML differentiation hierarchies including CD14+ monocyte-like and GMP-like AML. To assess the complex disease nature of AML, we performed functional analysis for each cluster to reveal interplay between multiple genomic aberrations such as NPM1, FLT3-ITD, DNMT3A mutations, complex chromosomal alterations, and the leukemia cell differentiation. Importantly, the multi-omics analysis performed not only connects previously identified molecular drivers and cell differentiation variations within AML, but also links them with observed cancer metabolomic reprogramming with their drug response implications. Moreover, our study also identified site-specific post-translational modifications previously not known in AML, highlighting the valuable insights and clinical relevance of these newly identified clusters. Citation Format: Alec Chu, Yi Hsiao, Yamei Deng, Chenwei Wang, Jennifer Kyle, Yongchao Dou, James C. Pino, Camilo Posso, Leanne Henry, Lijun Chen, Ginny Xiaohe Li, Tung-Shing Mamie Lih, Yifat Geffen, Fengchao Yu, Li Ding, Gil Omenn, Chandan Kumar, Saravana M. Dhanasekaran, Elie Traer, Jeffrey W. Tyner, Hui Zhang, Tao Liu, Sara Gosline, Bing Zhang, Arul Chinnaiyan, Alexey I. Nesvizhskii, Marcin Cieslik, The CPTAC Consortium. Proteogenomic and metabolomic characterization of acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7354.