Physiologic Expression of Sf3b1(K700E) Causes Impaired Erythropoiesis, Aberrant Splicing, and Sensitivity to Therapeutic Spliceosome Modulation

Cancer Cell. 2016 Sep 12;30(3):404-417. doi: 10.1016/j.ccell.2016.08.006.

Abstract

More than 80% of patients with the refractory anemia with ring sideroblasts subtype of myelodysplastic syndrome (MDS) have mutations in Splicing Factor 3B, Subunit 1 (SF3B1). We generated a conditional knockin mouse model of the most common SF3B1 mutation, Sf3b1(K700E). Sf3b1(K700E) mice develop macrocytic anemia due to a terminal erythroid maturation defect, erythroid dysplasia, and long-term hematopoietic stem cell (LT-HSC) expansion. Sf3b1(K700E) myeloid progenitors and SF3B1-mutant MDS patient samples demonstrate aberrant 3' splice-site selection associated with increased nonsense-mediated decay. Tet2 loss cooperates with Sf3b1(K700E) to cause a more severe erythroid and LT-HSC phenotype. Furthermore, the spliceosome modulator, E7017, selectively kills SF3B1(K700E)-expressing cells. Thus, SF3B1(K700E) expression reflects the phenotype of the mutation in MDS and may be a therapeutic target in MDS.

Publication types

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

MeSH terms

  • Animals
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Erythropoiesis / genetics
  • Erythropoiesis / physiology*
  • Hematopoietic Stem Cells / physiology
  • Humans
  • Mice
  • Mice, Transgenic
  • Myelodysplastic Syndromes / genetics
  • Myelodysplastic Syndromes / metabolism
  • Phosphoproteins / deficiency
  • Phosphoproteins / genetics*
  • Phosphoproteins / metabolism
  • Point Mutation
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • RNA Splicing
  • RNA Splicing Factors / deficiency
  • RNA Splicing Factors / genetics*
  • RNA Splicing Factors / metabolism
  • Spliceosomes / physiology*

Substances

  • DNA-Binding Proteins
  • Phosphoproteins
  • Proto-Oncogene Proteins
  • RNA Splicing Factors
  • SF3B1 protein, human
  • Sf3b1 protein, mouse
  • TET2 protein, human
  • Tet2 protein, mouse