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Long non-coding RNAs defining major subtypes of B cell precursor acute lymphoblastic leukemia

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Item Type:Preprint
Title:Long non-coding RNAs defining major subtypes of B cell precursor acute lymphoblastic leukemia
Creators Name:Rani James, A. and Schroeder, M.P. and Neumann, M. and Bastian, L. and Eckert, C. and Gökbuget, N. and Tanchez, J.O. and Schlee, C. and Isaakidis, K. and Schwartz, S. and Burmeister, T. and von Stackelberg, A. and Rieger, M.A. and Göllner, S. and Horstman, M. and Schrappe, M. and Kirschner-Schwabe, R. and Brüggemann, M. and Müller-Tidow, C. and Serve, H. and Akalin, A. and Baldus, C.D.
Abstract:Recent studies implicated that long non-coding RNAs (lncRNAs) may play a role in the progression and development of acute lymphoblastic leukemia, however, this role is not yet clear. In order to unravel the role of lncRNAs associated with B-cell precursor Acute Lymphoblastic Leukemia (BCP-ALL) subtypes, we performed transcriptome sequencing and DNA methylation array across 82 BCP-ALL samples from three molecular subtypes (DUX4, Ph-like, and Near Haploid or High Hyperdiploidy). Unsupervised clustering of BCP-ALL samples on the basis of their lncRNAs on transcriptome and DNA methylation profiles revealed robust clusters separating three molecular subtypes. Using extensive computational analysis, we developed a comprehensive catalog of 1235 aberrantly dysregulated BCP-ALL subtype-specific lncRNAs with altered expression and methylation patterns from three subtypes of BCP-ALL. By analyzing the co-expression of subtype-specific lncRNAs and protein-coding genes, we inferred key molecular processes in BCP-ALL subtypes. A strong correlation was identified between the DUX4 specific lncRNAs and activation of TGF-β and Hippo signaling pathways. Similarly, Ph-like specific lncRNAs were correlated with genes involved in activation of PI3K-AKT, mTOR, and JAK-STAT signaling pathways. Interestingly, the relapse-specific differentially expressed lncRNAs correlated with the activation of metabolic and signaling pathways. Finally, we showed a set of epigenetically altered lncRNAs facilitating the expression of tumor genes located at their cis location. Overall, our study provides a comprehensive set of novel subtype and relapse-specific lncRNAs in BCP-ALL. Our findings suggest a wide range of molecular pathways are associated with lncRNAs in BCP-ALL subtypes and provide a foundation for functional investigations that could lead to new therapeutic approaches.
Publisher:Cold Spring Harbor Laboratory (U.S.A.)
Article Number:365429
Date:9 July 2018
Official Publication:https://doi.org/10.1101/365429
Related to:
https://edoc.mdc-berlin.de/18004/Final version

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