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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

Leukemia (2019) | Download Citation

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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References

  1. 1.

    Schneider RK, Adema V, Heckl D, Jaras M, Mallo M, Lord AM, et al. Role of casein kinase 1A1 in the biology and targeted therapy of del(5q) MDS. Cancer Cell. 2014;26:509–20.

  2. 2.

    Hosono N, Makishima H, Mahfouz R, Przychodzen B, Yoshida K, Jerez A, et al. Recurrent genetic defects on chromosome 5q in myeloid neoplasms. Oncotarget. 2017;8:6483–95.

  3. 3.

    Heuser M, Meggendorfer M, Cruz MM, Fabisch J, Klesse S, Kohler L, et al. Frequency and prognostic impact of casein kinase 1A1 mutations in MDS patients with deletion of chromosome 5q. Leukemia. 2015;29:1942–5.

  4. 4.

    Bello E, Pellagatti A, Shaw J, Mecucci C, Kusec R, Killick S. et al. CSNK1A1 mutations and gene expression analysis in myelodysplastic syndromes with del(5q). Br J Haematol. 2015;171:210–4.

  5. 5.

    Polprasert C, Schulze I, Sekeres MA, Makishima H, Przychodzen B, Hosono N, et al. Inherited and somatic defects in DDX41 in myeloid neoplasms. Cancer Cell. 2015;27:658–70.

  6. 6.

    Wang J, Fernald AA, Anastasi J, Le Beau MM, Qian Z. Haploinsufficiency of Apc leads to ineffective hematopoiesis. Blood. 2010;115:3481–8.

  7. 7.

    Qian Z, Chen L, Fernald AA, Williams BO, Le Beau MM. A critical role for Apc in hematopoietic stem and progenitor cell survival. J Exp Med. 2008;205:2163–75.

  8. 8.

    Joslin JM, Fernald AA, Tennant TR, Davis EM, Kogan SC, Anastasi J, et al. Haploinsufficiency of EGR1, a candidate gene in the del(5q), leads to the development of myeloid disorders. Blood. 2007;110:719–26.

  9. 9.

    Grisendi S, Bernardi R, Rossi M, Cheng K, Khandker L, Manova K, et al. Role of nucleophosmin in embryonic development and tumorigenesis. Nature. 2005;437:147–53.

  10. 10.

    Lane SW, Sykes SM, Al-Shahrour F, Shterental S, Paktinat M, Lo Celso C, et al. The Apc(min) mouse has altered hematopoietic stem cell function and provides a model for MPD/MDS. Blood. 2010;115:3489–97.

  11. 11.

    Eisenmann KM, Dykema KJ, Matheson SF, Kent NF, DeWard AD, West RA, et al. 5q- myelodysplastic syndromes: chromosome 5q genes direct a tumor-suppression network sensing actin dynamics. Oncogene. 2009;28:3429–41.

  12. 12.

    Schneider RK, Schenone M, Ferreira MV, Kramann R, Joyce CE, Hartigan C, et al. Rps14 haploinsufficiency causes a block in erythroid differentiation mediated by S100A8 and S100A9. Nat Med. 2016;22:288–97.

  13. 13.

    Ebert BL, Pretz J, Bosco J, Chang CY, Tamayo P, Galili N, et al. Identification of RPS14 as a 5q- syndrome gene by RNA interference screen. Nature. 2008;451:335–9.

  14. 14.

    Starczynowski DT, Karsan A. Innate immune signaling in the myelodysplastic syndromes. Hematol Oncol Clin North Am. 2010;24:343–59.

  15. 15.

    Starczynowski DT, Kuchenbauer F, Argiropoulos B, Sung S, Morin R, Muranyi A, et al. Identification of miR-145 and miR-146a as mediators of the 5q- syndrome phenotype. Nat Med. 2010;16:49–58.

  16. 16.

    Barreyro L, Chlon TM, Starczynowski DT. Chronic immune response dysregulation in MDS pathogenesis. Blood. 2018;132:1553–60.

  17. 17.

    Ivy KS, Brent Ferrell P, Jr. Disordered immune regulation and its therapeutic targeting in myelodysplastic syndromes. Curr Hematol Malig Rep. 2018.

  18. 18.

    Ganan-Gomez I, Wei Y, Starczynowski DT, Colla S, Yang H, Cabrero-Calvo M, et al. Deregulation of innate immune and inflammatory signaling in myelodysplastic syndromes. Leukemia. 2015;29:1458–69.

  19. 19.

    Pronk CJ, Veiby OP, Bryder D, Jacobsen SE. Tumor necrosis factor restricts hematopoietic stem cell activity in mice: involvement of two distinct receptors. J Exp Med. 2011;208:1563–70.

  20. 20.

    Rosenfeld C, List A. A hypothesis for the pathogenesis of myelodysplastic syndromes: implications for new therapies. Leukemia. 2000;14:2–8.

  21. 21.

    Komrokji RS, Padron E, Ebert BL, List AF. Deletion 5q MDS: molecular and therapeutic implications. Best Pract Res Clin Haematol. 2013;26:365–75.

  22. 22.

    Zambetti NA, Ping Z, Chen S, Kenswil KJ, Mylona MA, Sanders MA, et al. Mesenchymal inflammation drives genotoxic stress in hematopoietic stem cells and predicts disease evolution in human pre-leukemia. Cell Stem Cell. 2016;19:613–27.

  23. 23.

    Popp HD, Naumann N, Brendel S, Henzler T, Weiss C, Hofmann WK, et al. Increase of DNA damage and alteration of the DNA damage response in myelodysplastic syndromes and acute myeloid leukemias. Leuk Res. 2017;57:112–8.

  24. 24.

    Nimer SD. Myelodysplastic syndromes. Blood. 2008;111:4841–51.

  25. 25.

    Hu X, Garcia M, Weng L, Jung X, Murakami JL, Kumar B, et al. Identification of a common mesenchymal stromal progenitor for the adult haematopoietic niche. Nat Commun. 2016;7:13095.

  26. 26.

    Chen S, Zambetti NA, Bindels EM, Kenswill K, Mylona AM, Adisty NM, et al. Massive parallel RNA sequencing of highly purified mesenchymal elements in low-risk MDS reveals tissue-context-dependent activation of inflammatory programs. Leukemia. 2016;30:1938–42.

  27. 27.

    Schneider RK, Mullally A, Dugourd A, Peisker F, Hoogenbozem R, Van Strien PMH. et al. Gli1+ mesenchymal stromal cells are a key driver of bone marrow fibrosis and an important cellular therapeutic target . Cell Stem Cell. 2017;20:785–800.

  28. 28.

    Mendez-Ferrer S, Michurina TV, Ferraro F, Mazloom AR, Macarthur BD, Lira SA, et al. Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature. 2010;466:829–34.

  29. 29.

    Stoddart A, Wang J, Hu C, Fernald AA, Davis EM, Cheng JX, et al. Inhibition of WNT signaling in the bone marrow niche prevents the development of MDS in the Apcdel/+ MDS mouse model. Blood. 2017;129:2959–70.

  30. 30.

    Chow A, Lucas D, Hidalgo A, Mendez-Ferrer S, Hashimoto D, Scheiermann C, et al. Bone marrow CD169+ macrophages promote the retention of hematopoietic stem and progenitor cells in the mesenchymal stem cell niche. J Exp Med. 2011;208:261–71.

  31. 31.

    Jaiswal S, Natarajan P, Silver AJ, Gibson CJ, Bick AG, Shvartz E, et al. Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease. N Engl J Med. 2017;377:111–21.

  32. 32.

    Rhyasen GW, Bolanos L, Fang J, Jerez A, Wunderlich M, Rigolino C, et al. Targeting IRAK1 as a therapeutic approach for myelodysplastic syndrome. Cancer Cell. 2013;24:90–104.

  33. 33.

    Keerthivasan G, Mei Y, Zhao B, Zhang L, Harris CE, Gao J, et al. Aberrant overexpression of CD14 on granulocytes sensitizes the innate immune response in mDia1 heterozygous del(5q) MDS. Blood. 2014;124:780–90.

  34. 34.

    Varney ME, Niederkorn M, Konno H, Matsumura T, Gohda J, Yoshida N, et al. Loss of Tifab, a del(5q) MDS gene, alters hematopoiesis through derepression of Toll-like receptor-TRAF6 signaling. J Exp Med. 2015;212:1967–85.

  35. 35.

    Mei Y, Zhao B, Basiorka AA, Yang J, Cao L, Zhang J, et al. Age-related inflammatory bone marrow microenvironment induces ineffective erythropoiesis mimicking del(5q) MDS. Leukemia. 2018;32:1023–33.

  36. 36.

    Boldin MP, Taganov KD, Rao DS, Yang L, Zhao JL, Kalwani M, et al. miR-146a is a significant brake on autoimmunity, myeloproliferation, and cancer in mice. J Exp Med. 2011;208:1189–201.

  37. 37.

    Zhao JL, Rao DS, Boldin MP, Taganov KD, O'Connell RM, Baltimore D. NF-kappaB dysregulation in microRNA-146a-deficient mice drives the development of myeloid malignancies. Proc Natl Acad Sci USA. 2011;108:9184–9.

  38. 38.

    Dimicoli S, Wei Y, Bueso-Ramos C, Yang H, Dinardo C, Jia Y, et al. Overexpression of the toll-like receptor (TLR) signaling adaptor MYD88, but lack of genetic mutation, in myelodysplastic syndromes. PLoS ONE. 2013;8:e71120.

  39. 39.

    Maratheftis CI, Andreakos E, Moutsopoulos HM, Voulgarelis M. Toll-like receptor-4 is up-regulated in hematopoietic progenitor cells and contributes to increased apoptosis in myelodysplastic syndromes. Clin Cancer Res. 2007;13:1154–60.

  40. 40.

    Fang J, Muto T, Kleppe M, Bolanos LC, Hueneman KM, Walker CS, et al. TRAF6 mediates basal activation of NF-kappaB necessary for hematopoietic stem cell homeostasis. Cell Rep. 2018;22:1250–62.

  41. 41.

    Stoddart A, Fernald AA, Wang J, Davis EM, Karrison T, Anastasi J, et al. Haploinsufficiency of del(5q) genes, Egr1 and Apc, cooperate with Tp53 loss to induce acute myeloid leukemia in mice. Blood. 2014;123:1069–78.

  42. 42.

    Stoddart A, Wang J, Fernald AA, Karrison T, Anastasi J, Le Beau MM. Cell intrinsic and extrinsic factors synergize in mice with haploinsufficiency for Tp53, and two human del(5q) genes, Egr1 and Apc. Blood. 2014;123:228–38.

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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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Author notes

  1. These authors contributed equally: Flavia Ribezzo, Inge A.M. Snoeren

Affiliations

  1. Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, RWTH Aachen University, Aachen, Germany

    • Flavia Ribezzo
    • , Susanne Ziegler
    • , Jacques Stoelben
    • , Monica Ventura Ferreira
    •  & Rebekka K. Schneider
  2. Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands

    • Inge A. M. Snoeren
    • , Patricia A. Olofsen
    • , Almira Henic
    • , Si Chen
    • , Ursula S. A. Stalmann
    • , Remco M. Hoogenboezem
    • , Marc H. G. P. Raaijmakers
    •  & Rebekka K. Schneider
  3. Institute of Pathology, Hannover Medical School, Hannover, Germany

    • Guntram Buesche
  4. Division of Nephrology and Clinical Immunology, RWTH Aachen University, Aachen, Germany

    • Rafael Kramann
  5. Department of Hematology, University Hospital Carl Gustav Carus Technical University, Dresden, Germany

    • Uwe Platzbecker
  6. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    • Benjamin L. Ebert

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Contributions

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.

Conflict of interest

The authors declare that they have no conflict of interest.

Corresponding author

Correspondence to Rebekka K. Schneider.

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DOI

https://doi.org/10.1038/s41375-018-0350-3