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Integrated analysis of relapsed B-cell precursor Acute Lymphoblastic Leukemia identifies subtype-specific cytokine and metabolic signatures

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Item Type:Article
Title:Integrated analysis of relapsed B-cell precursor Acute Lymphoblastic Leukemia identifies subtype-specific cytokine and metabolic signatures
Creators Name:Schroeder, M.P. and Bastian, L. and Eckert, C. and Gökbuget, N. and James, A.R. and Ortiz Tanchez, J. and Schlee, C. and Isaakidis, K. and Häupl, B. and Baum, K. and Migueles Lozano, O.A. and Kouidri, K. and Pan, K.T. and Urlaub, H. and Schwartz, S. and Burmeister, T. and von Stackelberg, A. and Hoelzer, D. and Pfeiffer, H. and Rieger, M.A. and Göllner, S. and Oellerich, T. and Horstman, M. and Schrappe, M. and Wolf, J. and Kirschner-Schwabe, R. and Brüggemann, M. and Müller-Tidow, C. and Serve, H. and Neumann, M. and Baldus, C.D.
Abstract:Recent efforts reclassified B-Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL) into more refined subtypes. Nevertheless, outcomes of relapsed BCP-ALL remain unsatisfactory, particularly in adult patients where the molecular basis of relapse is still poorly understood. To elucidate the evolution of relapse in BCP-ALL, we established a comprehensive multi-omics dataset including DNA-sequencing, RNA-sequencing, DNA methylation array and proteome MASS-spec data from matched diagnosis and relapse samples of BCP-ALL patients (n = 50) including the subtypes DUX4, Ph-like and two aneuploid subtypes. Relapse-specific alterations were enriched for chromatin modifiers, nucleotide and steroid metabolism including the novel candidates FPGS, AGBL and ZNF483. The proteome expression analysis unraveled deregulation of metabolic pathways at relapse including the key proteins G6PD, TKT, GPI and PGD. Moreover, we identified a novel relapse-specific gene signature specific for DUX4 BCP-ALL patients highlighting chemotaxis and cytokine environment as a possible driver event at relapse. This study presents novel insights at distinct molecular levels of relapsed BCP-ALL based on a comprehensive multi-omics integrated data set including a valuable proteomics data set. The relapse specific aberrations reveal metabolic signatures on genomic and proteomic levels in BCP-ALL relapse. Furthermore, the chemokine expression signature in DUX4 relapse underscores the distinct status of DUX4-fusion BCP-ALL.
Keywords:Cytokines, Genomics, Leukemic Gene Expression Regulation, Metabolic Networks and Pathways, Neoplasm Proteins, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, Proteomics
Source:Scientific Reports
Publisher:Nature Publishing Group
Page Range:4188
Date:12 March 2019
Official Publication:https://doi.org/10.1038/s41598-019-40786-1
PubMed:View item in PubMed

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