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Myelodysplasias

Insufficient stromal support in MDS results from molecular and functional deficits of mesenchymal stromal cells

Leukemia volume 27, pages 1841–1851 (2013)Cite this article

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Abstract

Ineffective hematopoiesis is a major characteristic of myelodysplastic syndromes (MDS) causing relevant morbidity and mortality. Mesenchymal stromal cells (MSC) have been shown to physiologically support hematopoiesis, but their contribution to the pathogenesis of MDS remains elusive. We show that MSC from patients across all MDS subtypes (n=106) exhibit significantly reduced growth and proliferative capacities accompanied by premature replicative senescence. Osteogenic differentiation was significantly reduced in MDS-derived MSC, indicated by cytochemical stainings and reduced expressions of Osterix and Osteocalcin. This was associated with specific methylation patterns that clearly separated MDS–MSC from healthy controls and showed a strong enrichment for biological processes associated with cellular phenotypes and transcriptional regulation. Furthermore, in MDS–MSC, we detected altered expression of key molecules involved in the interaction with hematopoietic stem and progenitor cells (HSPC), in particular Osteopontin, Jagged1, Kit-ligand and Angiopoietin as well as several chemokines. Functionally, this translated into a significantly diminished ability of MDS-derived MSC to support CD34+ HSPC in long-term culture-initiating cell assays associated with a reduced cell cycle activity. Taken together, our comprehensive analysis shows that MSC from all MDS subtypes are structurally, epigenetically and functionally altered, which leads to impaired stromal support and seems to contribute to deficient hematopoiesis in MDS.

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References

  1. Germing U, Aul C, Niemeyer CM, Haas R, Bennett JM . Epidemiology, classification and prognosis of adults and children with myelodysplastic syndromes. Ann Hematol 2008; 87: 691–699.

    Article  PubMed  Google Scholar 

  2. Neukirchen J, Blum S, Kuendgen A, Strupp C, Aivado M, Haas R et al. Platelet counts and haemorrhagic diathesis in patients with myelodysplastic syndromes. Eur J Haematol 2009; 83: 477–482.

    Article  PubMed  Google Scholar 

  3. Pang WW, Pluvinage JV, Price EA, Sridhar K, Arber DA, Greenberg PL et al. Hematopoietic stem cell and progenitor cell mechanisms in myelodysplastic syndromes. Proc Natl Acad Sci USA 2013; 110: 3011–3016.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Tehranchi R, Woll PS, Anderson K, Buza-Vidas N, Mizukami T, Mead AJ et al. Persistent malignant stem cells in del(5q) myelodysplasia in remission. N Engl JMed 2010; 363: 1025–1037.

    Article  CAS  Google Scholar 

  5. Will B, Zhou L, Vogler TO, Ben-Neriah S, Schinke C, Tamari R et al. Stem and progenitor cells in myelodysplastic syndromes show aberrant stage-specific expansion and harbor genetic and epigenetic alterations. Blood 2012; 120: 2076–2086.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Ayala F, Dewar R, Kieran M, Kalluri R . Contribution of bone microenvironment to leukemogenesis and leukemia progression. Leukemia 2009; 23: 2233–2241.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Raaijmakers MH . Myelodysplastic syndromes: revisiting the role of the bone marrow microenvironment in disease pathogenesis. Int J Hematol 2012; 95: 17–25.

    Article  PubMed  Google Scholar 

  8. 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: 829–834.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Shiozawa Y, Havens AM, Pienta KJ, Taichman RS . The bone marrow niche: habitat to hematopoietic and mesenchymal stem cells, and unwitting host to molecular parasites. Leukemia 2008; 22: 941–950.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Bianco P . Bone and the hematopoietic niche: a tale of two stem cells. Blood 2011; 117: 5281–5288.

    Article  CAS  PubMed  Google Scholar 

  11. Raaijmakers MH, Mukherjee S, Guo S, Zhang S, Kobayashi T, Schoonmaker JA et al. Bone progenitor dysfunction induces myelodysplasia and secondary leukaemia. Nature 2010; 464: 852–857.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Blau O, Baldus CD, Hofmann WK, Thiel G, Nolte F, Burmeister T et al. Mesenchymal stromal cells of myelodysplastic syndrome and acute myeloid leukemia patients have distinct genetic abnormalities compared with leukemic blasts. Blood 2011; 118: 5583–5592.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Blau O, Hofmann WK, Baldus CD, Thiel G, Serbent V, Schumann E et al. Chromosomal aberrations in bone marrow mesenchymal stroma cells from patients with myelodysplastic syndrome and acute myeloblastic leukemia. Exp Hematol 2007; 35: 221–229.

    Article  CAS  PubMed  Google Scholar 

  14. Flores-Figueroa E, Mayani H . Chromosomal abnormalities in marrow stromal cells from myelodysplastic syndromes (MDS). Blood 2006; 108: 3948 author reply -9.

    Article  CAS  PubMed  Google Scholar 

  15. Lopez-Villar O, Garcia JL, Sanchez-Guijo FM, Robledo C, Villaron EM, Hernandez-Campo P et al. Both expanded and uncultured mesenchymal stem cells from MDS patients are genomically abnormal, showing a specific genetic profile for the 5q- syndrome. Leukemia 2009; 23: 664–672.

    Article  CAS  PubMed  Google Scholar 

  16. Li X, Marcondes AM, Gooley TA, Deeg HJ . The helix-loop-helix transcription factor TWIST is dysregulated in myelodysplastic syndromes. Blood 2010; 116: 2304–2314.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Aanei CM, Eloae FZ, Flandrin-Gresta P, Tavernier E, Carasevici E, Guyotat D et al. Focal adhesion protein abnormalities in myelodysplastic mesenchymal stromal cells. Exp Cell Res 2011; 317: 2616–2629.

    Article  CAS  PubMed  Google Scholar 

  18. Flores-Figueroa E, Montesinos JJ, Flores-Guzman P, Gutierrez-Espindola G, Arana-Trejo RM, Castillo-Medina S et al. Functional analysis of myelodysplastic syndromes-derived mesenchymal stem cells. Leukemia research 2008; 32: 1407–1416.

    Article  CAS  PubMed  Google Scholar 

  19. Aanei CM, Flandrin P, Eloae FZ, Carasevici E, Guyotat D, Wattel E et al. Intrinsic growth deficiencies of mesenchymal stromal cells in myelodysplastic syndromes. Stem Cells Dev 2012; 21: 1604–1615.

    Article  CAS  PubMed  Google Scholar 

  20. Klaus M, Stavroulaki E, Kastrinaki MC, Fragioudaki P, Giannikou K, Psyllaki M et al. Reserves, functional, immunoregulatory, and cytogenetic properties of bone marrow mesenchymal stem cells in patients with myelodysplastic syndromes. Stem Cells Dev 2010; 19: 1043–1054.

    Article  CAS  PubMed  Google Scholar 

  21. Tennant GB, Walsh V, Truran LN, Edwards P, Mills KI, Burnett AK . Abnormalities of adherent layers grown from bone marrow of patients with myelodysplasia. Br JHaematol 2000; 111: 853–862.

    CAS  Google Scholar 

  22. Deeg HJ, Beckham C, Loken MR, Bryant E, Lesnikova M, Shulman HM et al. Negative regulators of hemopoiesis and stroma function in patients with myelodysplastic syndrome. Leuk Lymphoma 2000; 37: 405–414.

    Article  CAS  PubMed  Google Scholar 

  23. Tauro S, Hepburn MD, Peddie CM, Bowen DT, Pippard MJ . Functional disturbance of marrow stromal microenvironment in the myelodysplastic syndromes. Leukemia 2002; 16: 785–790.

    Article  CAS  PubMed  Google Scholar 

  24. Bruns I, Cadeddu RP, Brueckmann I, Frobel J, Geyh S, Bust S et al. Multiple myeloma-related deregulation of bone marrow-derived CD34(+) hematopoietic stem and progenitor cells. Blood 2012; 120: 2620–2630.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Castro-Malaspina H, Gay RE, Resnick G, Kapoor N, Meyers P, Chiarieri D et al. Characterization of human bone marrow fibroblast colony-forming cells (CFU-F) and their progeny. Blood 1980; 56: 289–301.

    CAS  PubMed  Google Scholar 

  26. Prata Kde L, Orellana MD, De Santis GC, Kashima S, Fontes AM, Carrara Rde C et al. Effects of high-dose chemotherapy on bone marrow multipotent mesenchymal stromal cells isolated from lymphoma patients. Exp Hematol 2010; 38: 292–300, e4.

    Article  PubMed  Google Scholar 

  27. Dvorakova J, Velebny V, Kubala L . Hyaluronan influence on the onset of chondrogenic differentiation of mesenchymal stem cells. Neuro Endocrinol Lett 2008; 29: 685–690.

    PubMed  Google Scholar 

  28. Schroeder T, Czibere A, Zohren F, Aivado M, Gattermann N, Germing U et al. Meningioma 1 gene is differentially expressed in CD34 positive cells from bone marrow of patients with myelodysplastic syndromes with the highest expression in refractory anemia with excess of blasts and secondary acute myeloid leukemia. Leuk Lymphoma 2009; 50: 1043–1046.

    Article  CAS  PubMed  Google Scholar 

  29. Bruns I, Czibere A, Fischer JC, Roels F, Cadeddu RP, Buest S et al. The hematopoietic stem cell in chronic phase CML is characterized by a transcriptional profile resembling normal myeloid progenitor cells and reflecting loss of quiescence. Leukemia 2009; 23: 892–899.

    Article  CAS  PubMed  Google Scholar 

  30. Gronniger E, Weber B, Heil O, Peters N, Stab F, Wenck H et al. Aging and chronic sun exposure cause distinct epigenetic changes in human skin. PLoS Genet 2010; 6: e1000971.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Bocker MT, Hellwig I, Breiling A, Eckstein V, Ho AD, Lyko F . Genome-wide promoter DNA methylation dynamics of human hematopoietic progenitor cells during differentiation and aging. Blood 2011; 117: e182–e189.

    Article  CAS  PubMed  Google Scholar 

  32. Teschendorff AE, Menon U, Gentry-Maharaj A, Ramus SJ, Weisenberger DJ, Shen H et al. Age-dependent DNA methylation of genes that are suppressed in stem cells is a hallmark of cancer. Genome Res 2010; 20: 440–446.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Jones PA . Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat Rev Genet 2012; 13: 484–492.

    Article  CAS  PubMed  Google Scholar 

  34. Hellman A, Chess A . Gene body-specific methylation on the active X chromosome. Science 2007; 315: 1141–1143.

    Article  CAS  PubMed  Google Scholar 

  35. Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006; 8: 315–317.

    Article  CAS  PubMed  Google Scholar 

  36. Frisch BJ, Ashton JM, Xing L, Becker MW, Jordan CT, Calvi LM . Functional inhibition of osteoblastic cells in an in vivo mouse model of myeloid leukemia. Blood 2012; 119: 540–550.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Isern J, Mendez-Ferrer S . Stem cell interactions in a bone marrow niche. Curr Osteoporos Rep 2011; 9: 210–218.

    Article  PubMed  Google Scholar 

  38. Varga G, Kiss J, Varkonyi J, Vas V, Farkas P, Paloczi K et al. Inappropriate Notch activity and limited mesenchymal stem cell plasticity in the bone marrow of patients with myelodysplastic syndromes. Pathol Oncol research: POR 2007; 13: 311–319.

    Article  CAS  PubMed  Google Scholar 

  39. Flores-Figueroa E, Arana-Trejo RM, Gutierrez-Espindola G, Perez-Cabrera A, Mayani H . Mesenchymal stem cells in myelodysplastic syndromes: phenotypic and cytogenetic characterization. Leuk Res 2005; 29: 215–224.

    Article  CAS  PubMed  Google Scholar 

  40. Zhao Z, Wang Z, Li Q, Li W, You Y, Zou P . The different immunoregulatory functions of mesenchymal stem cells in patients with low-risk or high-risk myelodysplastic syndromes. PloS One 2012; 7: e45675.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Schellenberg A, Hemeda H, Wagner W . Tracking of replicative senescence in mesenchymal stem cells by colony-forming unit frequency. Methods Mol Biol 2013; 976: 143–154.

    Article  CAS  PubMed  Google Scholar 

  42. Singh MK, Petry M, Haenig B, Lescher B, Leitges M, Kispert A . The T-box transcription factor Tbx15 is required for skeletal development. Mech Dev 2005; 122: 131–144.

    Article  CAS  PubMed  Google Scholar 

  43. Mellibovsky L, Diez A, Serrano S, Aubia J, Perez-Vila E, Marinoso ML et al. Bone remodeling alterations in myelodysplastic syndrome. Bone 1996; 19: 401–405.

    Article  CAS  PubMed  Google Scholar 

  44. Santamaria C, Muntion S, Roson B, Blanco B, Lopez-Villar O, Carrancio S et al. Impaired expression of DICER, DROSHA, SBDS and some microRNAs in mesenchymal stromal cells from myelodysplastic syndrome patients. Haematologica 2012; 97: 1218–1224.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Soenen-Cornu V, Tourino C, Bonnet ML, Guillier M, Flamant S, Kotb R et al. Mesenchymal cells generated from patients with myelodysplastic syndromes are devoid of chromosomal clonal markers and support short- and long-term hematopoiesis in vitro. Oncogene 2005; 24: 2441–2448.

    Article  CAS  PubMed  Google Scholar 

  46. Alvi S, Shaher A, Shetty V, Henderson B, Dangerfield B, Zorat F et al. Successful establishment of long-term bone marrow cultures in 103 patients with myelodysplastic syndromes. Leuk Res 2001; 25: 941–954.

    Article  CAS  PubMed  Google Scholar 

  47. Cortelezzi A, Cattaneo C, Cristiani S, Sarina B, Pomati M, Silvestris I et al. Low plasma stem cell factor levels correlate with in vitro leukemic growth in myelodysplastic syndromes. Leuk Res 1999; 23: 271–275.

    Article  CAS  PubMed  Google Scholar 

  48. Munugalavadla V, Kapur R . Role of c-Kit and erythropoietin receptor in erythropoiesis. Crit Rev Oncol/hematol 2005; 54: 63–75.

    Article  Google Scholar 

  49. Vallet S, Pozzi S, Patel K, Vaghela N, Fulciniti MT, Veiby P et al. A novel role for CCL3 (MIP-1alpha) in myeloma-induced bone disease via osteocalcin downregulation and inhibition of osteoblast function. Leukemia 2011; 25: 1174–1181.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Iancu-Rubin C, Mosoyan G, Wang J, Kraus T, Sung V, Hoffman R . Stromal cell-mediated inhibition of erythropoiesis can be attenuated by Sotatercept (ACE-011), an activin receptor type II ligand trap. Exp Hematol 2013; 41: 155–166, e17.

    Article  CAS  PubMed  Google Scholar 

  51. Zhou L, Nguyen AN, Sohal D, Ying Ma J, Pahanish P, Gundabolu K et al. Inhibition of the TGF-beta receptor I kinase promotes hematopoiesis in MDS. Blood 2008; 112: 3434–3443.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by the Leukämie Lymphom Liga e. V., Duesseldorf, Germany. We thank Annemarie Koch, Anke Boeckmann and Tanja Musch for their excellent technical assistance. We thank Johannes C. Fischer and Katharina Raba for their substantial technical support with the FACS analyses. SÖ is a PhD student of the HBIGS graduate school and supported by the PhD program ‘Disease Models and Drugs’ between the University of Heidelberg and the Mannheim University of Applied Sciences.

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Authors and Affiliations

  1. Department of Hematology, Oncology and Clinical Immunology, University of Duesseldorf, Medical Faculty, Duesseldorf, Germany

    S Geyh, R-P Cadeddu, J Fröbel, A Kündgen, R Fenk, I Bruns, N Gattermann, G Kobbe, U Germing, R Haas & T Schroeder

  2. Division of Epigenetics, DKFZ-ZMBH Alliance, German Cancer Research Center, Heidelberg, Germany

    S Öz & F Lyko

  3. Heidelberg, Germany

    B Brückner

  4. Department of Orthopedic Surgery, University of Duesseldorf, Medical Faculty, Duesseldorf, Germany

    C Zilkens

  5. Institute for Clinical Chemistry and Laboratory Diagnostics, University Hospital Duesseldorf, Duesseldorf, Germany

    D Hermsen

  6. German Cancer Consortium (DKTK),

    F Lyko

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  1. S Geyh
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Correspondence to T Schroeder.

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Additional information

Parts of this study have been presented at the 53rd American Society of Hematology (ASH) Annual Meeting, San Diego, CA, December 10–13, 2011 and at the Annual Meeting of the German-Austrian-Suisse Society of Hematology and Oncology (DGHO), October 19–23, 2012.

Author contributions

Conception and design: TS, RH, FL, SG. Provision of patients samples: UG, CZ, AK, GK, RF, TS. Experiments, collection and assembly of data: SG, TS, JF, R-PC, IB, SÖ. Data analysis and interpretation: TS, RH, SG, UG, NG, DH, FL, BB, JF, R-PC. Manuscript writing: TS, SG, RH, FL, BB. Final approval of the manuscript was given by all authors.

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Geyh, S., Öz, S., Cadeddu, RP. et al. Insufficient stromal support in MDS results from molecular and functional deficits of mesenchymal stromal cells. Leukemia 27, 1841–1851 (2013). https://doi.org/10.1038/leu.2013.193

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