Peptide microarray of pediatric acute myeloid leukemia is related to relapse and reveals involvement of DNA damage response and repair.

Hasan Mahmud,Tiny Meeuwsen-De Boer,Kim R Kampen,Frank J.G Scherpen,Victor Guryev,Steven M Kornblau,Arja Ter Elst,Eveline S.J.M De Bont,Valérie De Haas,Maikel M Peppelenbosch

doi:10.18632/oncotarget.27086

Abstract

The majority of acute myeloid leukemia (AML) patients suffer from relapse and the exact etiology of AML remains unclear. The aim of this study was to gain comprehensive insights into the activity of signaling pathways in AML. In this study, using a high-throughput PepChip™ Kinomics microarray system, pediatric AML samples were analyzed to gain insights of active signal transduction pathway. Unsupervised hierarchical cluster analysis separated the AML blast profiles into two clusters. These two clusters were independent of patient characteristics, whereas the cumulative incidence of relapse (CIR) was significantly higher in the patients belonging to cluster-2. In addition, cluster-2 samples showed to be significantly less sensitive to various chemotherapeutic drugs. The activated peptides in cluster-1 and cluster-2 reflected the activity of cell cycle regulation, cell proliferation, cell differentiation, apoptosis, PI3K/AKT, MAPK, metabolism regulation, transcription factors and GPCRs signaling pathways. The difference between two clusters might be explained by the higher cell cycle arrest response in cluster-1 patients and higher DNA repair mechanism in cluster-2 patients. In conclusion, our study identifies different signaling profiles in pediatric AML in relation with CIR involving DNA damage response and repair.

Highlights

Acute myeloid leukemia (AML) forms a spectrum of diseases that share clinical and pathological features
The peptide sequences of the 192 peptides with their basic functions based on the proteins they are derived from are given in Supplementary Table 4. These 192 activated peptides belonged to proteins involved in cell cycle regulation, cell proliferation, cell differentiation, apoptosis, PI3K/AKT signaling, mitogenactivated protein kinase signaling (MAPK), metabolism regulation, transcription factors or G-protein-coupled receptors (GPCRs) signaling
This study has demonstrated that peptide microarray profiling of acute myeloid leukemia (AML) samples provides significant details about AML signaling and identified two clusters associated with DNA damage response and repair system, resulting in significantly different cumulative incidence of relapse (CIR)

Summary

Introduction

Acute myeloid leukemia (AML) forms a spectrum of diseases that share clinical and pathological features. Extensive research, including genomic sequencing in the TCGA project, has revealed many previously unknown recurrent mutations and additional mechanistic insights such as alternations in the epigenetic status www.oncotarget.com during leukemogenesis. Based on these new findings classification has evolved from the French-AmericanBritish system (FAB), which was driven by morphology and later surface markers, to the current World Health Organization (WHO) classification which incorporates the current well-defined karyotypical, mutations and genetic abnormalities. AML leukemogenesis and the regulation of leukemic cell proliferation and survival is the net result of all genetic, epigenetic and environmental factors present in the leukemic blast manifesting through canonical or non-canonical utilization of the existing signal transduction pathways in those cells. Improved therapy of AML will require therapeutic agents directed against the perturbed pathways downstream of these events

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