Splicing Factor Gene Mutations in the Myelodysplastic Syndromes: Impact on Disease Phenotype and Therapeutic Applications

Adv Biol Regul. 2017 Jan;63:59-70. doi: 10.1016/j.jbior.2016.08.001. Epub 2016 Aug 21.

Abstract

Splicing factor gene mutations are the most frequent mutations found in patients with the myeloid malignancy myelodysplastic syndrome (MDS), suggesting that spliceosomal dysfunction plays a major role in disease pathogenesis. The aberrantly spliced target genes and deregulated cellular pathways associated with the commonly mutated splicing factor genes in MDS (SF3B1, SRSF2 and U2AF1) are being identified, illuminating the molecular mechanisms underlying MDS. Emerging data from mouse modeling studies indicate that the presence of splicing factor gene mutations can lead to bone marrow hematopoietic stem/myeloid progenitor cell expansion, impaired hematopoiesis and dysplastic differentiation that are hallmarks of MDS. Importantly, recent evidence suggests that spliceosome inhibitors and splicing modulators may have therapeutic value in the treatment of splicing factor mutant myeloid malignancies.

Keywords: Mutations; Myelodysplastic syndromes; RNA splicing; Splicing factor gene.

Publication types

  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Cell Proliferation
  • Gene Expression
  • Hematopoietic Stem Cells / drug effects
  • Hematopoietic Stem Cells / metabolism
  • Hematopoietic Stem Cells / pathology
  • Humans
  • Mice
  • Mutation*
  • Myelodysplastic Syndromes / drug therapy
  • Myelodysplastic Syndromes / genetics*
  • Myelodysplastic Syndromes / metabolism
  • Myelodysplastic Syndromes / pathology
  • Phenotype
  • Phosphoproteins / antagonists & inhibitors*
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism
  • Pyrans / pharmacology*
  • RNA Splicing / drug effects
  • RNA Splicing Factors / antagonists & inhibitors*
  • RNA Splicing Factors / genetics
  • RNA Splicing Factors / metabolism
  • Serine-Arginine Splicing Factors / antagonists & inhibitors*
  • Serine-Arginine Splicing Factors / genetics
  • Serine-Arginine Splicing Factors / metabolism
  • Spiro Compounds / pharmacology*
  • Spliceosomes / drug effects
  • Spliceosomes / metabolism
  • Spliceosomes / pathology
  • Splicing Factor U2AF / antagonists & inhibitors*
  • Splicing Factor U2AF / genetics
  • Splicing Factor U2AF / metabolism

Substances

  • Antineoplastic Agents
  • Phosphoproteins
  • Pyrans
  • RNA Splicing Factors
  • SF3B1 protein, human
  • Spiro Compounds
  • Splicing Factor U2AF
  • U2AF1 protein, human
  • spliceostatin A
  • SRSF2 protein, human
  • Serine-Arginine Splicing Factors