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

Ulf Schmitz, Jaynish S. Shah, Bijay P. Dhungel, Geoffray Monteuuis, Phuc Loi Luu, Veronika Petrova, Cynthia Metierre, Shalima S. Nair, Charles G. Bailey, Verity A. Saunders, Ali G. Turhan, Deborah L. White, Susan Branford, Susan J. Clark, Timothy P. Hughes, Justin J.L. Wong, John E.J. Rasko

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

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.

Original languageEnglish
Article number3738
Pages (from-to)1-19
Number of pages19
JournalCancers
Volume12
Issue number12
DOIs
Publication statusPublished or Issued - Dec 2020

Keywords

  • Alternative splicing
  • BCR-ABL1
  • CML
  • Cancer
  • DNA methylation
  • Epigenetics
  • Histone modifications
  • Intron retention
  • Transcriptomic complexity

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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