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Graft-Versus-Host Disease

Numerical impairment of nestin+ bone marrow niches in acute GvHD after allogeneic hematopoietic stem cell transplantation for AML

Bone Marrow Transplantation volume 50, pages 1453–1458 (2015)Cite this article

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Abstract

The nestin+ perivascular bone marrow (BM) stem cell niche (N+SCN) may be involved in GvHD. To investigate whether acute GvHD (aGvHD) reduces the number of N+SCN, we examined patients with AML who had undergone allogeneic hematopoietic stem cell transplantation. In the test cohort (n=8), the number of N+SCN per mm2 in BM biopsies was significantly reduced in aGvHD patients at the time of aGvHD compared with patients who did not have aGvHD (1.2±0.78 versus 2.6±0.93, P=0.04). In the validation cohort (n=40), the number of N+SCN was reduced (1.9±0.99 versus 2.6±0.90 N+SCN/mm2, P=0.05) in aGvHD patients. Receiver operating curves suggested that the cutoff score that best discriminated between patients with and without aGvHD was 2.29 N+SCN/mm2. Applying this cutoff score, 9/11 patients with clinically relevant aGvHD (⩾grade 2) and 13/20 with any type of GvHD had decreased N+SCN numbers compared with only 10/29 patients without clinically relevant aGvHD (P=0.007) and 6/20 patients without any type of GvHD (P=0.028). In patients tracked over time, N+SCN density returned to normal after aGvHD resolved or remained stable in patients who did not have aGvHD. Our results show a decrease in the number of N+SCN in aGvHD.

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References

  1. Passweg JR, Baldomero H, Peters C, Gaspar HB, Cesaro S, Dreger P et al. European Society for Blood and Marrow Transplantation EBMT. Hematopoietic SCT in Europe: data and trends in 2012 with special consideration of pediatric transplantation. Bone Marrow Transplant 2014; 49: 744–750.

    Article  Google Scholar 

  2. Gratwohl A, Baldomero H . Trends of hematopoietic stem cell transplantation in the third millennium. Curr Opin Hematol 2009; 16: 420–426.

    Article  Google Scholar 

  3. Socié G, Blazar BR . Acute graft-versus-host disease: from the bench to the bedside. Blood 2009; 114: 4327–4336.

    Article  Google Scholar 

  4. Ruutu T, Gratwohl A, de Witte T, Afanasyev B, Apperley J, Bacigalupo A et al. Prophylaxis and treatment of GVHD: EBMT-ELN working group recommendations for a standardized practice. Bone Marrow Transplant 2014; 49: 168–173.

    Article  CAS  Google Scholar 

  5. von Bonin M, Bornhäuser M . Concise review: the bone marrow niche as a target of graft versus host disease. Stem Cells 2014; 32: 1420–1428.

    Article  CAS  Google Scholar 

  6. Tichelli A, Gratwohl A . Vascular endothelium as 'novel' target of graft-versus-host disease. Best Pract Res Clin Haematol 2008; 21: 139–148.

    Article  CAS  Google Scholar 

  7. Biedermann BC, Sahner S, Gregor M, Tsakiris DA, Jeanneret C, Pober JS et al. Endothelial injury mediated by cytotoxic T lymphocytes and loss of microvessels in chronic graft versus host disease. Lancet 2002; 359: 2078–2083.

    Article  Google Scholar 

  8. Biedermann BC, Tsakiris DA, Gregor M, Pober JS, Gratwohl A . Combining altered levels of effector transcripts in circulating T cells with a marker of endothelial injury is specific for active graft-versus-host disease. Bone Marrow Transplant 2003; 32: 1077–1084.

    Article  CAS  Google Scholar 

  9. Medinger M, Skoda R, Gratwohl A, Theocharides A, Buser A, Heim D et al. Angiogenesis and vascular endothelial growth factor-/receptor expression in myeloproliferative neoplasms: correlation with clinical parameters and JAK2-V617F mutational status. Br J Haematol 2009; 146: 150–157.

    Article  CAS  Google Scholar 

  10. Medinger M, Tzankov A, Kern J, Pircher A, Hermann M, Ott HW et al. Increased Dkk3 protein expression in platelets and megakaryocytes of patients with myeloproliferative neoplasms. Thromb Haemost 2011; 105: 72–80.

    Article  CAS  Google Scholar 

  11. Penack O, Henke E, Suh D, King CG, Smith OM, Na IK et al. Inhibition of neovascularization to simultaneously ameliorate graft-vs-host disease and decrease tumor growth. J Natl Cancer Inst 2010; 102: 894–908.

    Article  CAS  Google Scholar 

  12. Penack O, Socié G, van den Brink MR . The importance of neovascularization and its inhibition for allogeneic hematopoietic stem cell transplantation. Blood 2011; 117: 4181–4189.

    Article  CAS  Google Scholar 

  13. Medinger M, Tichelli A, Bucher C, Halter J, Dirnhofer S, Rovo A et al. GVHD after allogeneic haematopoietic SCT for AML: angiogenesis, vascular endothelial growth factor and VEGF receptor expression in the BM. Bone Marrow Transplant 2013; 48: 715–721.

    Article  CAS  Google Scholar 

  14. Yao Y, Song X, Cheng H, Tang G, Hu X, Zhou H et al. Dysfunction of bone marrow vascular niche in acute graft-versus-host disease after MHC-haploidentical bone marrow transplantation. PLoS One 2014; 9: e104607.

    Article  Google Scholar 

  15. Suzuki S, Namiki J, Shibata S, Mastuzaki Y, Okano H . The neural stem/progenitor cell marker nestin is expressed in proliferative endothelial cells, but not in mature vasculature. J Histochem Cytochem 2010; 58: 721–773.

    Article  CAS  Google Scholar 

  16. Lendahl U, Zimmerman LB, McKay RD . CNS stem cells express a new class of intermediate filament protein. Cell 1990; 60: 585–595.

    Article  CAS  Google Scholar 

  17. Matsuda Y, Hagio M, Ishiwata T . Nestin: a novel angiogenesis marker and possible target for tumor angiogenesis. World J Gastroenterol 2013; 19: 42–48.

    Article  CAS  Google Scholar 

  18. Pallari HM, Lindqvist J, Torvaldson E, Ferraris SE, He T, Sahlgren C et al. Nestin as a regulator of Cdk5 in differentiating myoblasts. Mol Biol Cell 2011; 22: 1539–1549.

    Article  CAS  Google Scholar 

  19. Matsuda Y, Hagio M, Ishiwata T . Nestin in gastrointestinal and other cancers: Effects on cells and tumor angiogenesis. World J Gastroenterol 2011; 17: 409–418.

    Article  Google Scholar 

  20. Wiese C, Rolletschek A, Kania G, Blyszczuk P, Tarasov KV, Tarasova Y et al. Nestin expression—a property of multi-lineage progenitor cells? Cell Mol Life Sci 2004; 61: 2510–2522.

    Article  CAS  Google Scholar 

  21. Arranz L, Sánchez-Aguilera A, Martín-Pérez D, Isern J, Langa X, Tzankov A et al. Neuropathy of haematopoietic stem cell niche is essential for myeloproliferative neoplasms. Nature 2014; 512: 78–81.

    Article  CAS  Google Scholar 

  22. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H et al WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. IARC Press: Lyon, France, 2008.

    Google Scholar 

  23. Cheson BD, Bennett JM, Kopecky KJ, Büchner T, Willman CL, Estey EH et al. International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol 2003; 21: 4642–4649.

    Article  Google Scholar 

  24. Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J et al. 1994 Consensus conference on acute GVHD grading. Bone Marrow Transplant 1995; 15: 825–828.

    CAS  Google Scholar 

  25. Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant 2005; 11: 945–956.

    Article  Google Scholar 

  26. Tzankov A, Zlobec I, Went P, Robl H, Hoeller S, Dirnhofer S . Prognostic immunophenotypic biomarker studies in diffuse large B cell lymphoma with special emphasis on rational determination of cut-off scores. Leuk Lymphoma 2010; 51: 199–212.

    Article  CAS  Google Scholar 

  27. Drobyski WR, Morse HC 3rd, Burns WH, Casper JT, Sandford G . Protection from lethal murine graft-versus-host disease without compromise of alloengraftment using transgenic donor T cells expressing a thymidine kinase suicide gene. Blood 2001; 97: 2506–2513.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Hematology, University Hospital Basel, Basel, Switzerland

    M Medinger, A Jakab, J Halter, A Buser, C Bucher & J Passweg

  2. GMP Facility, University Hospital Basel, Basel, Switzerland

    W Krenger

  3. Institute of Pathology, University Hospital Basel, Basel, Switzerland

    A Tzankov

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  1. M Medinger
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  7. J Passweg
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Correspondence to M Medinger.

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Medinger, M., Krenger, W., Jakab, A. et al. Numerical impairment of nestin+ bone marrow niches in acute GvHD after allogeneic hematopoietic stem cell transplantation for AML. Bone Marrow Transplant 50, 1453–1458 (2015). https://doi.org/10.1038/bmt.2015.189

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