Telomere dysfunction drives aberrant hematopoietic differentiation and myelodysplastic syndrome

Cancer Cell. 2015 May 11;27(5):644-57. doi: 10.1016/j.ccell.2015.04.007.

Abstract

Myelodysplastic syndrome (MDS) risk correlates with advancing age, therapy-induced DNA damage, and/or shorter telomeres, but whether telomere erosion directly induces MDS is unknown. Here, we provide the genetic evidence that telomere dysfunction-induced DNA damage drives classical MDS phenotypes and alters common myeloid progenitor (CMP) differentiation by repressing the expression of mRNA splicing/processing genes, including SRSF2. RNA-seq analyses of telomere dysfunctional CMP identified aberrantly spliced transcripts linked to pathways relevant to MDS pathogenesis such as genome stability, DNA repair, chromatin remodeling, and histone modification, which are also enriched in mouse CMP haploinsufficient for SRSF2 and in CD34(+) CMML patient cells harboring SRSF2 mutation. Together, our studies establish an intimate link across telomere biology, aberrant RNA splicing, and myeloid progenitor differentiation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / genetics*
  • Haploinsufficiency
  • Hematopoiesis / genetics*
  • Humans
  • Mice
  • Myelodysplastic Syndromes / genetics*
  • Myelodysplastic Syndromes / pathology
  • Nuclear Proteins / genetics
  • RNA Splicing
  • Ribonucleoproteins / genetics
  • Serine-Arginine Splicing Factors
  • Telomere*

Substances

  • Nuclear Proteins
  • Ribonucleoproteins
  • SRSF2 protein, human
  • Serine-Arginine Splicing Factors

Associated data

  • GEO/GSE62393