RT Journal Article
SR Electronic
T1 Long non-coding RNAs defining major subtypes of B cell precursor acute lymphoblastic leukemia
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 365429
DO 10.1101/365429
A1 Alva Rani James
A1 Michael P Schroeder
A1 Martin Neumann
A1 Lorenz Bastian
A1 Cornelia Eckert
A1 Nicola Gökbuget
A1 Jutta Ortiz Tanchez
A1 Cornelia Schlee
A1 Konstandina Isaakidis
A1 Stefan Schwartz
A1 Thomas Burmeister
A1 Arend von Stackelberg
A1 Michael A Rieger
A1 Stefanie Göllner
A1 Martin Horstman
A1 Martin Schrappe
A1 Renate Kirschner-Schwabe
A1 Monika Brüggemann
A1 Carsten Müller-Tidow
A1 Hubert Serve
A1 Altuna Akalin
A1 Claudia D Baldus
YR 2018
UL http://biorxiv.org/content/early/2018/07/09/365429.abstract
AB 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.Author Summary Acute lymphoblastic leukemia is a heterogeneous blood cancer, with multiple molecular subtypes, and with high relapse rate. We are far from the complete understanding of the rationale behind these subtypes and high relapse rate. Long non-coding (lncRNAs) has emerged as a novel class of RNA due to its diverse mechanism in cancer development and progression. LncRNAs does not code for proteins and represent around 70% of human transcripts. Recently, there are a number of studies used lncRNAs expression profile in the classification of various cancers subtypes and displayed their correlation with genomic, epigenetic, pathological and clinical features in diverse cancers. Therefore, lncRNAs can account for heterogeneity and has independent prognostic value in various cancer subtypes. However, lncRNAs defining the molecular subtypes of BCP-ALL are not portrayed yet. Here, we describe a set of relapse and subtype-specific lncRNAs from three major BCP-ALL subtypes and define their potential functions and epigenetic regulation. Our data uncover the diverse mechanism of action of lncRNAs in BCP-ALL subtypes defining how lncRNAs are involved in the pathogenesis of disease and the relevance in the stratification of BCP-ALL subtypes.