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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Increased expression of S100A8 in MDS-derived macrophages induces S100A8 expression in neighboring MSCs.
“Using an MDS mouse model and patient samples, we demonstrated that increased expression of S100A8 in MDS-derived macrophages induces S100A8 expression in neighboring MSCs.”
From Inflammatory bone marrow microenvironment (2019) · cites this paper as [70]
Macrophages and monocytes are increased in chronic inflammatory states in aging and in myeloid malignancies and might be an important contributor to remodeling of the BM microenvironment in inflammation and hematopoietic disease.
“Macrophages and monocytes, as cells of the innate immune response, are increased in chronic inflammatory states in aging and in myeloid malignancies and might be an important contributor to the remodeling of the BM microenvironment in inflammation and hematopoietic disease (anemia, BM failure, and also leukemia).70”
From Inflammatory bone marrow microenvironment (2019) · cites this paper as [70]
Increased expression of S100A8 in stromal cells is directly linked to loss of their hematopoiesis-supporting capacity.
“We further directly linked the increased expression of S100A8 in stromal cells to loss of their hematopoiesissupporting capacity.70”
From Inflammatory bone marrow microenvironment (2019) · cites this paper as [70]
Rps14 haploinsufficiency in a murine model of del(5q) MDS leads to increased expression of S100A8 and S100A9 in mutant erythroblasts, monocytes, and macrophages, the main regulatory cells of the erythroid niche.
“In our previous work, we demonstrated that Rps14 haploinsufficiency in a murine model of del(5q) MDS leads to increased expression of S100A8 and S100A9 in mutant erythroblasts, monocytes, and macrophages, the main regulatory cells of the erythroid niche.70”
From Inflammatory bone marrow microenvironment (2019) · cites this paper as [70]
S100A8 is responsible for the erythroid-differentiation defect: 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.
“We demonstrated specifically that S100A8 is responsible for the erythroid-differentiation defect 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.”
From Inflammatory bone marrow microenvironment (2019) · cites this paper as [70]
Increased expression of S100A8/S100A9 was observed in the mesenchymal niche in del(5q) MDS.
“Interestingly, we also observed increased expression of S100A8/S100A9 in the mesenchymal niche in del(5q) MDS.70”
From Inflammatory bone marrow microenvironment (2019) · cites this paper as [70]
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References 43 · Cited by 51
- Authors
- Ribezzo, F., Snoeren, I. A. M., Ziegler, S., Stoelben, J., Olofsen, P. A., Henic, A., Ferreira, M. V., Chen, S., Stalmann, U. S. A., Buesche, G., Hoogenboezem, R. M., Kramann, R., Platzbecker, U., Raaijmakers, M. H. G. P., Ebert, B. L., & Schneider, R. K.
- Affiliations
- RWTH Aachen University (DE)
- Erasmus MC Cancer Institute (NL)
- Medizinische Hochschule Hannover (DE)
- University Hospital Carl Gustav Carus (DE)
- Dana-Farber Cancer Institute (US)
- Corresponding author
- Schneider, Rebekka K.
- ORCID
- Venue
- Leukemia
- Published
- 2019-01-16
- Volume
- 33
- Issue
- 7
- Pages
- 1759-1772
- ISSN
- 0887-6924 (ISSN-L)
- 1476-5551
- OpenAlex
- W2908703054
- Cited by
- 51
- References
- 43
- Citations by year
- 2026: 2 · 2025: 7 · 2024: 7 · 2023: 5 · 2022: 10 · 2021: 9 · 2020: 5 · 2019: 6
- FWCI
- 5.34
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Leukemia (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- RWTH Publications (RWTH Aachen) (submittedVersion)
- Funders
- KWF Kankerbestrijding (11031/2017-1)
- EC | European Research Council (ERC-StG 757339)
- European Hematology Association (John Goldman Clinical Research grant)
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Blood disorders and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Keywords
- 5q- syndrome, RPS14, CSNK1A1, miR-145, miR-146a, haploinsufficiency, innate immune activation, macrophages, S100A8, anemia, megakaryocytes, hematopoietic microenvironment, hematopoietic stem cells, phagocytosis, bone marrow
- MeSH terms
- Anemia, Anemia, Macrocytic, Animals, Bone Marrow, Chromosome Deletion, Chromosomes, Human, Pair 5, Erythropoiesis, Female, Hematopoietic Stem Cells, Humans, Megakaryocytes, Phenotype, Ribosomal Proteins, Tumor Cells, Cultured, Mice, Knockout, MicroRNAs, Calgranulin A, Casein Kinase Ialpha, Mice, Haploinsufficiency, Tumor Microenvironment
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