Widespread aberrant alternative splicing despite molecular remission in chronic myeloid leukaemia patients

Schmitz, Ulf, Shah, Jaynish S., Dhungel, Bijay P., Monteuuis, Geoffray, Luu, Phuc-Loi, Petrova, Veronika, Metierre, Cynthia, Nair, Shalima S., Bailey, Charles G., Saunders, Verity A., Turhan, Ali G., White, Deborah L., Branford, Susan, Clark, Susan J., Hughes, Timothy P., Wong, Justin J.-L., and Rasko, John E.J. (2020) Widespread aberrant alternative splicing despite molecular remission in chronic myeloid leukaemia patients. Cancers, 12 (12). 3738.

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DOI: 10.3390%2Fcancers12123738
View at Publisher Website: https://doi.org/10.3390%2Fcancers1212373...
 
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Abstract

Vast transcriptomics and epigenomics changes are characteristic of human cancers, including leukaemia. At remission, we assume that these changes normalise so that omics-profiles resemble those of healthy individuals. However, an in-depth transcriptomic and epigenomic analysis of cancer remission has not been undertaken. A striking exemplar of targeted remission induction occurs in chronic myeloid leukaemia (CML) following tyrosine kinase inhibitor (TKI) therapy. Using RNA sequencing and whole-genome bisulfite sequencing, we profiled samples from chronic-phase CML patients at diagnosis and remission and compared these to healthy donors. Remarkably, our analyses revealed that abnormal splicing distinguishes remission samples from normal controls. This phenomenon is independent of the TKI drug used and in striking contrast to the normalisation of gene expression and DNA methylation patterns. Most remarkable are the high intron retention (IR) levels that even exceed those observed in the diagnosis samples. Increased IR affects cell cycle regulators at diagnosis and splicing regulators at remission. We show that aberrant splicing in CML is associated with reduced expression of specific splicing factors, histone modifications and reduced DNA methylation. Our results provide novel insights into the changing transcriptomic and epigenomic landscapes of CML patients during remission. The conceptually unanticipated observation of widespread aberrant alternative splicing after remission induction warrants further exploration. These results have broad implications for studying CML relapse and treating minimal residual disease.

Item ID: 68970
Item Type: Article (Research - C1)
ISSN: 2072-6694
Keywords: transcriptomic complexity; alternative splicing; intron retention; DNA methylation;epigenetics; BCR-ABL1; histone modifications; CML; cancer
Copyright Information: © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open accessarticle distributed under the terms and conditions of the Creative Commons Attribution(CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Funders: National Health and Medical Research Council of Australia (NHMRC)
Projects and Grants: NHMRC #1177305, NHMRC #1128175, NHMRC #1129901, NHMRC #1126306, NHMRC APP1104425, NHMRC APP1135949
Date Deposited: 15 Sep 2021 02:03
FoR Codes: 32 BIOMEDICAL AND CLINICAL SCIENCES > 3211 Oncology and carcinogenesis > 321106 Haematological tumours @ 50%
31 BIOLOGICAL SCIENCES > 3102 Bioinformatics and computational biology > 310204 Genomics and transcriptomics @ 40%
31 BIOLOGICAL SCIENCES > 3101 Biochemistry and cell biology > 310114 Systems biology @ 10%
SEO Codes: 28 EXPANDING KNOWLEDGE > 2801 Expanding knowledge > 280103 Expanding knowledge in the biomedical and clinical sciences @ 80%
28 EXPANDING KNOWLEDGE > 2801 Expanding knowledge > 280102 Expanding knowledge in the biological sciences @ 20%
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