Global Proteomic Profiling of Pediatric AML: A Pilot Study

SIMPLE SUMMARY: The second most common childhood leukemia, acute myeloid leukemia (AML), is a heterogeneous disease with a poor prognosis. In order to improve outcomes, efforts to understand the genomic/transcriptomic landscape of AML have been performed. However, there is a significant gap in our understanding of leukemic cell proteomics. In comparison to the proteome, the transcriptome alone cannot adequately represent the biological functions within cells and it is often not a target for immediate drug development. In the current study, we investigated cytogenetic differences at the proteomic level and sought potential predictive biomarkers and druggable proteins. ABSTRACT: Acute Myeloid Leukemia (AML) is a heterogeneous disease with several recurrent cytogenetic abnormalities. Despite genomics and transcriptomics profiling efforts to understand AML’s heterogeneity, studies focused on the proteomic profiles associated with pediatric AML cytogenetic features remain limited. Furthermore, the majority of biological functions within cells are operated by proteins (i.e., enzymes) and most drugs target the proteome rather than the genome or transcriptome, thus, highlighting the significance of studying proteomics. Here, we present our results from a pilot study investigating global proteomic profiles of leukemic cells obtained at diagnosis from 16 pediatric AML patients using a robust TMT-LC/LC-MS/MS platform. The proteome profiles were compared among patients with or without core binding factor (CBF) translocation indicated by a t(8;21) or inv(16) cytogenetic abnormality, minimal residual disease status at the end of the first cycle of chemotherapy (MRD1), and in vitro chemosensitivity of leukemic cells to cytarabine (Ara-C LC50). Our results established proteomic differences between CBF and non-CBF AML subtypes, providing insights to AML subtypes physiology, and identified potential druggable proteome targets such as THY1 (CD90), NEBL, CTSF, COL2A1, CAT, MGLL (MAGL), MACROH2A2, CLIP2 (isoform 1 and 2), ANPEP (CD13), MMP14, and AK5.