Abstract

Impaired erythropoiesis in the deletion 5q (del(5q)) subtype of myelodysplastic syndrome (MDS) has been linked to heterozygous deletion of RPS14, which encodes the ribosomal protein small subunit 14. We generated mice with conditional inactivation of Rps14 and demonstrated an erythroid differentiation defect that is dependent on the tumor suppressor protein p53 (encoded by Trp53 in mice) and is characterized by apoptosis at the transition from polychromatic to orthochromatic erythroblasts. This defect resulted in age-dependent progressive anemia, megakaryocyte dysplasia and loss of hematopoietic stem cell (HSC) quiescence. As assessed by quantitative proteomics, mutant erythroblasts expressed higher levels of proteins involved in innate immune signaling, notably the heterodimeric S100 calcium-binding proteins S100a8 and S100a9. S100a8—whose expression was increased in mutant erythroblasts, monocytes and macrophages—is functionally involved in the erythroid defect caused by the Rps14 deletion, as addition of recombinant S100a8 was sufficient to induce a differentiation defect in wild-type erythroid cells, and genetic inactivation of S100a8 expression rescued the erythroid differentiation defect of Rps14-haploinsufficient HSCs. Our data link Rps14 haploinsufficiency in del(5q) MDS to activation of the innate immune system and induction of S100A8-S100A9 expression, leading to a p53-dependent erythroid differentiation defect.

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Acknowledgements

This work was supported by the US National Institutes of Health (NIH) (grant no. R01HL082945; B.L.E.), a Gabrielle's Angel Award (B.L.E.), a Leukemia and Lymphoma Society Scholar and Specialized Center of Research (SCOR) award (B.L.E.), the German Research Foundation (DFG1188/3-1; R.K.S.), a Max Eder fellowship provided by the German Cancer Aid (Deutsche Krebshilfe, grant no. 111750; R.K.S.), the Edward P. Evans Foundation (R.K.S.) and the German Cluster of Excellence program Regenerative Biology to Reconstructive Therapy (REBIRTH; to G.B.). We thank D. Haase (Georg-August-Universität Göttingen) for the cytogenetic (karyotype) analysis in individuals with del(5q) MDS. This work was supported by the confocal microscope facility, a core facility of the Interdisciplinary Center for Clinical Research (Interdisziplinäres Zentrum für klinische Forschung; IZKF) Aachen, within the Faculty of Medicine at RWTH Aachen University.

Author information

Affiliations

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

    • Rebekka K Schneider
    • , Michelle C Chen
    • , Christopher S Waters
    • , Edwin Chen
    • , Lisa P Chu
    • , R Coleman Lindsley
    •  & Benjamin L Ebert
  2. Department of Hematology, Hemostaseology, Oncology and Stem Cell Transplantation, University Hospital Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen, Aachen, Germany.

    • Rebekka K Schneider
    • , Monica Ventura Ferreira
    • , Fabian Beier
    • , Tim H Brümmendorf
    •  & Steven A Carr
  3. Broad Institute of Harvard University and the Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • Monica Schenone
    • , Christina Hartigan
    •  & Benjamin L Ebert
  4. Renal Division, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Rafael Kramann
  5. Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • Cailin E Joyce
    • , Carl D Novina
    •  & R Coleman Lindsley
  6. Department of Hematology, Oncology and Clinical Immunology, Heinrich Heine University, Düsseldorf, Germany.

    • Ulrich Germing
  7. Department of Medicine I, University Hospital Carl Gustav Carus, University of Technology, Dresden, Germany.

    • Uwe Platzbecker
  8. Institute of Pathology, Hannover Medical School, Hannover, Germany.

    • Guntram Büsche
  9. Institute of Pathology, University Hospital Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen, Aachen, Germany.

    • Ruth Knüchel

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Contributions

R.K.S., R.C.L., S.A.C. and B.L.E. designed experiments; R.K.S., M.S., R. Kramann, M.V.F., C.E.J., C.H., F.B., M.C.C., E.C., C.S.W., C.D.N. and L.P.C. performed experiments and analyzed data; F.B., T.H.B., U.G., U.P., R. Knüchel and G.B. collected patient samples and clinical information, reviewed bone marrow biopsies and analyzed data; R.K.S. and B.L.E. wrote the manuscript; and all authors provided critical reviews of the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Benjamin L Ebert.

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    Samples included in the proteomic analysis

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DOI

https://doi.org/10.1038/nm.4047

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