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Myelodysplastic syndrome

Rps14, Csnk1a1 and miRNA145/miRNA146a deficiency cooperate in the clinical phenotype and activation of the innate immune system in the 5q- syndrome

Abstract

RPS14, CSNK1A1, and miR-145 are universally co-deleted in the 5q- syndrome, but mouse models of each gene deficiency recapitulate only a subset of the composite clinical features. We analyzed the combinatorial effect of haploinsufficiency for Rps14, Csnk1a1, and miRNA-145, using mice with genetically engineered, conditional heterozygous inactivation of Rps14 and Csnk1a1 and stable knockdown of miR-145/miR-146a. Combined Rps14/Csnk1a1/miR-145/146a deficiency recapitulated the cardinal features of the 5q- syndrome, including (1) more severe anemia with faster kinetics than Rps14 haploinsufficiency alone and (2) pathognomonic megakaryocyte morphology. Macrophages, regulatory cells of erythropoiesis and the innate immune response, were significantly increased in Rps14/Csnk1a1/miR-145/146a deficient mice as well as in 5q- syndrome patient bone marrows and showed activation of the innate immune response, reflected by increased expression of S100A8, and decreased phagocytic function. We demonstrate that Rps14/Csnk1a1/miR-145 and miR-146a deficient macrophages alter the microenvironment and induce S100A8 expression in the mesenchymal stem cell niche. The increased S100A8 expression in the mesenchymal niche was confirmed in 5q- syndrome patients. These data indicate that intrinsic defects of the 5q- syndrome hematopoietic stem cell directly alter the surrounding microenvironment, which in turn affects hematopoiesis as an extrinsic mechanism.

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Acknowledgements

This work was supported by the European Hematology Association (EHA; John Goldman Clinical Research grant), a research grant of the MPN foundation (2017 MPNRF/LLS Award), a KWF Kankerbestrijding young investigator grant (11031/2017–1, Bas Mulder Award; Dutch Cancer Foundation), a Celgene research grant (DEU-077) and a grant of the European Research Council (ERC) (deFIBER; ERC-StG 757339), all to RKS. We thank Nina Welters for excellent technical assistance.

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FR, SZ, IAMS, JS, PAO, AH, MVF, USA, and RK carried out experiments, analyzed the data, and reviewed the manuscript. GB selected patient specimen, analyzed, and interpreted histopathology and reviewed the manuscript, UP, SC, and MHGPR provided patient specimen, analyzed data, and reviewed the manuscript. BLE contributed to experimental design, data interpretation, and writing of the manuscript. RKS designed and carried out experiments, analyzed results, and wrote the manuscript.

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Correspondence to Rebekka K. Schneider.

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Ribezzo, F., Snoeren, I.A.M., Ziegler, S. et al. Rps14, Csnk1a1 and miRNA145/miRNA146a deficiency cooperate in the clinical phenotype and activation of the innate immune system in the 5q- syndrome. Leukemia 33, 1759–1772 (2019). https://doi.org/10.1038/s41375-018-0350-3

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