Global Proteomic Profiling of Pediatric AML: A Pilot Study.

Nam H K Nguyen,Stanley Pounds,Jeffrey E Rubnitz,Jatinder K Lamba,Haiyan Tan,Junmin Peng,Huiyun Wu,Xueyuan Cao

doi:10.3390/cancers13133161

Abstract

Simple SummaryThe 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.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.

Highlights

Acute myeloid leukemia (AML) is the second most common childhood leukemia with five-year survival rates of approximately 60% [1]
The 16 pediatric Acute Myeloid Leukemia (AML) were randomly selected from AML02 patients with bone marrow aspirate available, balancing core binding factor (CBF) vs. non-CBF, MRD1 status, and Ara-C LC50 level
Sixteen pediatric AML patients treated on the AML02 clinical trial were randomly selected and included in this study

Summary

Introduction

Acute myeloid leukemia (AML) is the second most common childhood leukemia with five-year survival rates of approximately 60% [1]. Recent advances in next-generation sequencing technologies have significantly expanded researchers’ understanding of pediatric AML heterogeneity. Most of these studies have focused on differential transcriptomic profiles [4,5,6]. Uncovering genetic mutations and abnormal gene expressions is less likely to lead to the immediate therapeutic option, as most druggable targets are proteins rather than genes/transcripts. The characterization of the proteomic landscape is critical. It is well established that the molecular landscape of pediatric AML is distinct from adult AML with age-specific mutational interactions, highlighting the need for proteomic investigation in the pediatric population in order to further characterize the heterogeneity and develop treatments with age-specific targeted therapies for pediatric AML [14]

Methods

Results

Conclusion