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Mutations in spliceosome genes and therapeutic opportunities in myeloid malignancies

Justin Taylor1,2, Stanley C Lee1

  • 1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.

Genes, Chromosomes & Cancer
|July 24, 2019
PubMed

Insights

Dysregulated RNA splicing, driven by mutations in spliceosome components, contributes to diseases like cancer. This review explores these mechanisms and novel therapeutic strategies targeting splicing.

Area of Science:

  • Molecular Biology
  • Genetics
  • Oncology

Background:

  • RNA splicing, crucial for gene expression, has been studied for over 40 years.
  • Dysregulation of pre-messenger RNA (pre-mRNA) splicing is implicated in various human diseases, including neurodegenerative disorders and cancer.
  • Somatic mutations in spliceosome components are frequently identified in myeloid malignancies, highlighting their role in disease.

Purpose of the Study:

  • To review the mechanisms by which mutant splicing factors impact RNA splicing.
  • To discuss the functional and pathophysiological consequences of altered splicing in disease.
  • To summarize recent therapeutic advances targeting splicing pathways and novel oligonucleotide-based therapies.

Main Methods:

  • Review of current literature on RNA splicing mechanisms and disease associations.
  • Analysis of functional studies on mutant splicing factors and their impact on gene expression.
  • Examination of emerging therapeutic strategies and technologies for modulating aberrant splicing.

Main Results:

  • Mutant splicing factors can alter both constitutive and alternative splicing patterns.
  • Splicing alterations contribute significantly to the pathogenesis of myeloid malignancies and potentially other diseases.
  • Targeting splicing offers promising avenues for novel therapeutic interventions.

Conclusions:

  • Understanding the intricate mechanisms of splicing dysregulation is key to developing effective treatments.
  • Targeting splicing catalysis and regulatory proteins represents a promising therapeutic strategy.
  • Oligonucleotide-based therapies show potential for modulating disease-associated spliced isoforms.
Keywords:
RNA splicingSF3B1SRSF2U2AF1myeloid leukemia

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