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Nat Med DOI:10.1038/nm.4047

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

Publication TypeJournal Article
Year of Publication2016
AuthorsSchneider, RK, Schenone, M, Ferreira, MVentura, Kramann, R, Joyce, CE, Hartigan, C, Beier, F, Brümmendorf, TH, Germing, U, Platzbecker, U, Büsche, G, Knüchel, R, Chen, MC, Waters, CS, Chen, E, Chu, LP, Novina, CD, R Lindsley, C, Carr, SA, Ebert, BL
JournalNat Med
Volume22
Issue3
Pages288-97
Date Published2016 Mar
ISSN1546-170X
KeywordsAnemia, Animals, Blotting, Western, Bone Marrow, Calgranulin A, Calgranulin B, Cytokines, Disease Models, Animal, Erythroid Precursor Cells, Erythropoiesis, Flow Cytometry, Fluorescent Antibody Technique, Haploinsufficiency, Hematopoietic Stem Cells, Humans, Immunity, Innate, Immunohistochemistry, In Situ Hybridization, Fluorescence, In Vitro Techniques, Mass Spectrometry, Megakaryocytes, Mice, Mice, Knockout, Microscopy, Confocal, Myelodysplastic Syndromes, Ribosomal Proteins, Tumor Suppressor Protein p53
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.

URLhttp://dx.doi.org/10.1038/nm.4047
DOI10.1038/nm.4047
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/26878232?dopt=Abstract

Alternate JournalNat. Med.
PubMed ID26878232
PubMed Central IDPMC4870050
Grant ListP01 CA066996 / CA / NCI NIH HHS / United States
R01 HL082945 / HL / NHLBI NIH HHS / United States
R01HL082945 / HL / NHLBI NIH HHS / United States