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Rps14 haploinsufficiency causes a block in erythroid differentiation mediated by S100A8 and S100A9

Rebekka K Schneider1,2, Monica Schenone3, Monica Ventura Ferreira2

  • 1Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Nature Medicine
|February 16, 2016
PubMed

Insights

Haploinsufficiency of RPS14 in del(5q) myelodysplastic syndrome causes anemia by activating innate immunity. This leads to a p53-dependent erythroid differentiation defect, mediated by S100A8 and S100A9 proteins.

Area of Science:

  • Hematology
  • Molecular Biology
  • Immunology

Background:

  • Myelodysplastic syndromes (MDS) are a group of clonal hematopoietic stem cell disorders.
  • The deletion 5q (del(5q)) subtype of MDS is characterized by impaired erythropoiesis.
  • Heterozygous deletion of RPS14 is linked to the erythroid defect in del(5q) MDS.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying the erythroid differentiation defect in Rps14-haploinsufficient mice.
  • To determine the role of p53 and innate immune signaling in this process.

Main Methods:

  • Conditional inactivation of Rps14 in mice.
  • Analysis of erythroid differentiation and apoptosis.
  • Quantitative proteomics to identify differentially expressed proteins.
  • Functional studies using recombinant S100a8 and genetic inactivation of S100a8.

Main Results:

  • Rps14 inactivation caused an erythroid differentiation defect dependent on p53, leading to apoptosis.
  • Anemia, megakaryocyte dysplasia, and loss of hematopoietic stem cell quiescence were observed.
  • Increased expression of S100a8 and S100a9 was found in mutant erythroblasts and myeloid cells.
  • S100a8 functionally contributed to the erythroid defect, and its inactivation rescued the phenotype.

Conclusions:

  • Rps14 haploinsufficiency in del(5q) MDS activates innate immune signaling.
  • Induced S100A8-S100A9 expression mediates a p53-dependent erythroid differentiation defect.
  • This provides a molecular link between genetic alterations and immune dysregulation in MDS.

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