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Profile of fibrosis-related gene transcripts and megakaryocytic changes in the bone marrow of myelodysplastic syndromes with fibrosis

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Abstract

Bone marrow fibrosis (MF) in myelodysplastic syndromes (MDS) is associated with an adverse prognosis. It is likely that molecular changes similar to those in primary myelofibrosis (PMF) lead to MDS-MF, but gene expression profiling has not yet been carried out. We analysed bone marrow biopsy samples by PCR, qPCR (45 transcripts per sample), and immunohistochemistry from MDS patients with fibrosis (n = 70/119; including 19/70 MF0 > MF follow-up cases), MDS without fibrosis (n = 49/119), and 33 controls. SRSF2 and JAK2 mutations were detectable in up to 13% including 3/19 follow-up cases with evidence of clonal evolution during MF progression. MDS-MF showed increased expression of thrombospondin 1 (THBS1), TIMP metallopeptidase inhibitor 1 (TIMP1), transforming growth factor beta 1 (TGFB1), matrix metallopeptidases 2 and 14 (MMP2, MMP14), SMAD family members 3 and 4 (SMAD3, SMAD4), and miR-146b. Paralleling MF progression, a subfraction of follow-up cases showed megakaryocytic changes with increased CD42b+ pro-platelet deposition in the bone marrow. In summary, fibrosis in MDS-MF and PMF shows many molecular and morphological similarities.

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References

  1. Ramos F, Robledo C, Izquierdo-García FM, Suárez-Vilela D, Benito R, Fuertes M, Insunza A, Barragán E, del Rey M, García-Ruiz de Morales JM, Tormo M, Salido E, Zamora L, Pedro C, Sánchez-del-Real J, Díez-Campelo M, del Cañizo C, Sanz GF, Hernández-Rivas JM, Spanish Group for Myelodysplastic Syndromes (GESMD) (2016) Bone marrow fibrosis in myelodysplastic syndromes: a prospective evaluation including mutational analysis. Oncotarget 7:30492–30503

    Article  Google Scholar 

  2. Machherndl-Spandl S, Sega W, Bösmüller H, Germing U, Gruber C, Nachtkamp K, Reinecke P, Sperr WR, Wimazal F, Müllauer L, Sotlar K, Horny HP, Tüchler H, Valent P, Krieger O (2014) Prognostic impact of blast cell counts in dysplastic bone marrow disorders (MDS and CMML I) with concomitant fibrosis. Ann Hematol 93:57–64

    Article  Google Scholar 

  3. Fu B, Ok CY, Goswami M, Xei W, Jaso JM, Muzzafar T, Bueso-Ramos C, Verstovsek S, Garcia-Manero G, Medeiros LJ, Wang SA (2013) The clinical importance of moderate/severe bone marrow fibrosis in patients with therapy-related myelodysplastic syndromes. Ann Hematol 92:1335–1343

    Article  Google Scholar 

  4. Kröger N, Zabelina T, van Biezen A, Brand R, Niederwieser D, Martino R et al (2011) Allogeneic stem cell transplantation for myelodysplastic syndromes with bone marrow fibrosis. Haematologica 96:291–297

    Article  Google Scholar 

  5. Della Porta MG, Malcovati L, Boveri E, Travaglino E, Pietra D, Pascutto C, Passamonti F, Invernizzi R, Castello A, Magrini U, Lazzarino M, Cazzola M (2009) Clinical relevance of bone marrow fibrosis and CD34-positive cell clusters in primary myelodysplastic syndromes. J Clin Oncol 27:754–762

    Article  Google Scholar 

  6. Buesche G, Teoman H, Wilczak W, Ganser A, Hecker H, Wilkens L, Göhring G, Schlegelberger B, Bock O, Georgii A, Kreipe H (2008) Marrow fibrosis predicts early fatal marrow failure in patients with myelodysplastic syndromes. Leukemia 22:313–322

    Article  CAS  Google Scholar 

  7. Scott BL, Storer BE, Greene JE, Hackman RC, Appelbaum FR, Deeg HJ (2007) Marrow fibrosis as a risk factor for posttransplantation outcome in patients with advanced myelodysplastic syndrome or acute myeloid leukemia with multilineage dysplasia. Biol Blood Marrow Transplant 13:345–354

    Article  Google Scholar 

  8. Mondet J, Hussein K, Mossuz P (2015) Circulating cytokine levels as markers of inflammation in Philadelphia negative myeloproliferative neoplasms: diagnostic and prognostic interest. Mediat Inflamm 2015:670580

    Article  Google Scholar 

  9. Kvasnicka HM, Beham-Schmid C, Bob R, Dirnhofer S, Hussein K, Kreipe H, Kremer M, Schmitt-Graeff A, Schwarz S, Thiele J, Werner M, Stein H (2016) Problems and pitfalls in grading of bone marrow fibrosis, collagen deposition and osteosclerosis—a consensus-based study. Histopathology 68:905–915

    Article  Google Scholar 

  10. Gangat N, Patnaik MM, Tefferi A (2016) Myelodysplastic syndromes: contemporary review and how we treat. Am J Hematol 91:76–89

    Article  CAS  Google Scholar 

  11. Sochacki AL, Fischer MA, Savona MR (2016) Therapeutic approaches in myelofibrosis and myelodysplastic/myeloproliferative overlap syndromes. Onco Targets Ther 9:2273–2286

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Lehmann U, Bartels S, Hasemeier B, Geffers R, Schlue J, Büsche G et al (2013) SRSF2 mutation is present in the hypercellular and prefibrotic stage of primary myelofibrosis. Blood 121:4011–4012

    Article  CAS  Google Scholar 

  13. Hussein K, Stucki-Koch A, Göhring G, Kreipe H, Suttorp M (2017) Increased megakaryocytic proliferation, pro-platelet deposition and expression of fibrosis-associated factors in children with chronic myeloid leukaemia with bone marrow fibrosis. Leukemia 31:1540–1546

    Article  CAS  Google Scholar 

  14. Hussein K, Stucki-Koch A, Alchalby H, Triviai I, Kröger N, Kreipe H (2016) Cytokine expression pattern in bone marrow microenvironment after allogeneic stem cell transplantation in primary myelofibrosis. Biol Blood Marrow Transplant 22:644–650

    Article  CAS  Google Scholar 

  15. Hussein K, Theophile K, Büsche G, Schlegelberger B, Göhring G, Kreipe H, Bock O (2010) Aberrant microRNA expression pattern in myelodysplastic bone marrow cells. Leuk Res 34:1169–1174

    Article  CAS  Google Scholar 

  16. Muth M, Büsche G, Bock O, Hussein K, Kreipe H (2010) Aberrant proplatelet formation in chronic myeloproliferative neoplasms. Leuk Res 34:1424–1429

    Article  Google Scholar 

  17. Muth M, Engelhardt BM, Kröger N, Hussein K, Schlué J, Büsche G, Kreipe HH, Bock O (2011) Thrombospondin-1 (TSP-1) in primary myelofibrosis (PMF)—a megakaryocyte-derived biomarker which largely discriminates PMF from essential thrombocythemia. Ann Hematol 90:33–40

    Article  CAS  Google Scholar 

  18. Jonigk D, Theophile K, Hussein K, Bock O, Lehmann U, Bockmeyer CL, Gottlieb J, Fischer S, Simon A, Welte T, Maegel L, Kreipe H, Laenger F (2010) Obliterative airway remodelling in transplanted and non-transplanted lungs. Virchows Arch 457:369–380

    Article  Google Scholar 

  19. Stucki-Koch A, Hauck G, Kreipe H, Hussein K (2015) MicroRNA expression profiles in BCR-ABL-negative primary myelofibrosis with chromosome 7q defects. J Hematop 8:203–208

    Article  Google Scholar 

  20. Bock O, Muth M, Theophile K, Winter M, Hussein K, Büsche G, Kröger N, Kreipe H (2009) Identification of new target molecules PTK2, TGFBR2 and CD9 overexpressed during advanced bone marrow remodelling in primary myelofibrosis. Br J Haematol 146:510–520

    Article  CAS  Google Scholar 

  21. Bock O, Höftmann J, Theophile K, Hussein K, Wiese B, Schlué J, Kreipe H (2008) Bone morphogenetic proteins are overexpressed in the bone marrow of primary myelofibrosis and are apparently induced by fibrogenic cytokines. Am J Pathol 172:951–960

    Article  CAS  Google Scholar 

  22. Loghavi S, Al-Ibraheemi A, Zuo Z, Garcia-Manero G, Yabe M, Wang SA et al (2015) TP53 overexpression is an independent adverse prognostic factor in de novo myelodysplastic syndromes with fibrosis. Br J Haematol 171:91–99

    Article  CAS  Google Scholar 

  23. Bektas O, Uner A, Buyukasik Y, Uz B, Bozkurt S, Eliacik E, Işik A, Haznedaroglu IC, Goker H, Demiroglu H, Aksu S, Ozcebe OI, Sayinalp N (2015) Clinical and pathological correlations of marrow PUMA and P53 expressions in myelodysplastic syndromes. APMIS 123:445–451

    Article  CAS  Google Scholar 

  24. Yang L, Qian Y, Eksioglu E, Epling-Burnette PK, Wei S (2015) The inflammatory microenvironment in MDS. Cell Mol Life Sci 72:1959–1966

    Article  CAS  Google Scholar 

  25. Kittang AO, Sand K, Brenner AK, Rye KP, Bruserud Ø (2016) The systemic profile of soluble immune mediators in patients with myelodysplastic syndromes. Int J Mol Sci 17:E1080

    Article  Google Scholar 

  26. Ha JS, Jung HR (2015) Up-regulation of MicroRNA 146b is associated with myelofibrosis in myeloproliferative neoplasms. Ann Clin Lab Sci 45:308–314

    CAS  PubMed  Google Scholar 

  27. Hussein K, Theophile K, Dralle W, Wiese B, Kreipe H, Bock O (2009) MicroRNA expression profiling of megakaryocytes in primary myelofibrosis and essential thrombocythemia. Platelets 20:391–400

    Article  CAS  Google Scholar 

  28. Paterson MR, Kriegel AJ (2017) MiR-146a/b: a family with shared seeds and different roots. Physiol Genomics 49:243–252

    Article  CAS  Google Scholar 

  29. Curtale G, Mirolo M, Renzi TA, Rossato M, Bazzoni F, Locati M (2013) Negative regulation of Toll-like receptor 4 signaling by IL-10-dependent microRNA-146b. Proc Natl Acad Sci U S A 110:11499–11504

    Article  CAS  Google Scholar 

  30. Budi EH, Duan D, Derynck R (2017) Transforming growth factor-β receptors and Smads: regulatory complexity and functional versatility. Trends Cell Biol 27:658–672

    Article  CAS  Google Scholar 

  31. Kim MJ, Park SY, Chang HR, Jung EY, Munkhjargal A, Lim JS, Lee MS, Kim Y (2017) Clinical significance linked to functional defects in bone morphogenetic protein type 2 receptor, BMPR2. BMB Rep 50:308–317

    Article  CAS  Google Scholar 

  32. Akiyama T, Matsunaga T, Terui T, Miyanishi K, Tanaka I, Sato T, Kuroda H, Takimoto R, Takayama T, Kato J, Yamauchi N, Kogawa K, Sakamaki S, Hirayama Y, Kohda K, Niitsu Y (2005) Involvement of transforming growth factor-beta and thrombopoietin in the pathogenesis of myelodysplastic syndrome with myelofibrosis. Leukemia 19:1558–1566

    Article  CAS  Google Scholar 

  33. Bock O, Loch G, Schade U, von Wasielewski R, Schlué J, Kreipe H (2005) Aberrant expression of transforming growth factor beta-1 (TGF beta-1) per se does not discriminate fibrotic from non-fibrotic chronic myeloproliferative disorders. J Pathol 205:548–557

    Article  CAS  Google Scholar 

  34. Åström M, Hahn-Strömberg V, Zetterberg E, Vedin I, Merup M, Palmblad J (2015) X-linked thrombocytopenia with thalassemia displays bone marrow reticulin fibrosis and enhanced angiogenesis: comparisons with primary myelofibrosis. Am J Hematol 90:E44–E48

    Article  Google Scholar 

  35. Niino D, Tsuchiya T, Tomonaga M, Miyazaki Y, Ohshima K (2013) Clinicopathological features of acute megakaryoblastic leukaemia: relationship between fibrosis and platelet-derived growth factor. Pathol Int 63:141–149

    Article  CAS  Google Scholar 

  36. Machlus KR, Johnson KE, Kulenthirarajan R, Forward JA, Tippy MD, Soussou TS, el-Husayni SH, Wu SK, Wang S, Watnick RS, Italiano JE, Battinelli EM (2016) CCL5 derived from platelets increases megakaryocyte proplatelet formation. Blood 127:921–926

    Article  CAS  Google Scholar 

  37. Garimella R, Kacena MA, Tague SE, Wang J, Horowitz MC, Anderson HC (2007) Expression of bone morphogenetic proteins and their receptors in the bone marrow megakaryocytes of GATA-1(low) mice: a possible role in osteosclerosis. J Histochem Cytochem 55:745–752

    Article  CAS  Google Scholar 

  38. Bock O, Neuse J, Hussein K, Brakensiek K, Buesche G, Buhr T, Wiese B, Kreipe H (2006) Aberrant collagenase expression in chronic idiopathic myelofibrosis is related to the stage of disease but not to the JAK2 mutation status. Am J Pathol 169:471–481

    Article  CAS  Google Scholar 

  39. Eliades A, Papadantonakis N, Bhupatiraju A, Burridge KA, Johnston-Cox HA, Migliaccio AR, Crispino JD, Lucero HA, Trackman PC, Ravid K (2011) Control of megakaryocyte expansion and bone marrow fibrosis by lysyl oxidase. J Biol Chem 286:27630–27638

    Article  CAS  Google Scholar 

  40. Nakayama S, Yokote T, Hiraoka N, Akioka T, Nishiwaki U, Miyoshi T, Iwaki K, Fumimoto A, Masuda Y, Hatooka J, Fujimoto M, Nishimura Y, Tsuji M (2017) Transforming growth factor β- and interleukin 13-producing mast cells are associated with fibrosis in bone marrow. Hum Pathol 62:180–186

    Article  CAS  Google Scholar 

  41. Battula VL, Chen Y, Cabreira Mda G, Ruvolo V, Wang Z, Ma W et al (2013) Connective tissue growth factor regulates adipocyte differentiation of mesenchymal stromal cells and facilitates leukemia bone marrow engraftment. Blood 122:357–366

    Article  CAS  Google Scholar 

  42. Tamura S, Suzuki-Inoue K, Tsukiji N, Shirai T, Sasaki T, Osada M, Satoh K, Ozaki Y (2016) Podoplanin-positive periarteriolar stromal cells promote megakaryocyte growth and proplatelet formation in mice by CLEC-2. Blood 127:1701–1710

    Article  CAS  Google Scholar 

  43. Yanase M, Ikeda H, Ogata I, Matsui A, Noiri E, Tomiya T, Arai M, Inoue Y, Tejima K, Nagashima K, Nishikawa T, Shibata M, Ikebe M, Rojkind M, Fujiwara K (2003) Functional diversity between Rho-kinase- and MLCK-mediated cytoskeletal actions in a myofibroblast-like hepatic stellate cell line. Biochem Biophys Res Commun 305:223–228

    Article  CAS  Google Scholar 

  44. Meinders M, Kulu DI, van de Werken HJ, Hoogenboezem M, Janssen H, Brouwer RW et al (2015) Sp1/Sp3 transcription factors regulate hallmarks of megakaryocyte maturation and platelet formation and function. Blood 125:1957–1967

    Article  CAS  Google Scholar 

  45. Travaglino E, Benatti C, Malcovati L, Della Porta MG, Gallì A, Bonetti E et al (2008) Biological and clinical relevance of matrix metalloproteinases 2 and 9 in acute myeloid leukaemias and myelodysplastic syndromes. Eur J Haematol 80:216–226

    Article  Google Scholar 

  46. Lekovic D, Gotic M, Skoda R, Beleslin-Cokic B, Milic N, Mitrovic-Ajtic O, Nienhold R, Sefer D, Suboticki T, Buac M, Markovic D, Diklic M, Cokic VP (2017) Bone marrow microvessel density and plasma angiogenic factors in myeloproliferative neoplasms: clinicopathological and molecular correlations. Ann Hematol 96:393–404

    Article  CAS  Google Scholar 

  47. Pruneri G, Bertolini F, Soligo D, Carboni N, Cortelezzi A, Ferrucci PF, Buffa R, Lambertenghi-Deliliers G, Pezzella F (1999) Angiogenesis in myelodysplastic syndromes. Br J Cancer 81:1398–1401

    Article  CAS  Google Scholar 

  48. Babarović E, Valković T, Štifter S, Budisavljević I, Seili-Bekafigo I, Duletić-Načinović A, Lučin K, Jonjić N (2012) Assessment of bone marrow fibrosis and angiogenesis in monitoring patients with multiple myeloma. Am J Clin Pathol 137:870–878

    Article  Google Scholar 

  49. Eklund L, Kangas J, Saharinen P (2017) Angiopoietin-Tie signalling in the cardiovascular and lymphatic systems. Clin Sci (Lond) 131:87–103

    Article  CAS  Google Scholar 

  50. Chong HC, Tan CK, Huang RL, Tan NS (2012) Matricellular proteins: a sticky affair with cancers. J Oncol 2012:351089

    Article  Google Scholar 

  51. Rogers NM, Sharifi-Sanjani M, Yao M, Ghimire K, Bienes-Martinez R, Mutchler SM, Knupp HE, Baust J, Novelli EM, Ross M, St. Croix C, Kutten JC, Czajka CA, Sembrat JC, Rojas M, Labrousse-Arias D, Bachman TN, Vanderpool RR, Zuckerbraun BS, Champion HC, Mora AL, Straub AC, Bilonick RA, Calzada MJ, Isenberg JS (2017) TSP1-CD47 signaling is upregulated in clinical pulmonary hypertension and contributes to pulmonary arterial vasculopathy and dysfunction. Cardiovasc Res 113:15–29

    Article  Google Scholar 

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Acknowledgments

The authors thank Mrs. Gillian Teicke (Institute of Human Genetics, MHH) for editing the manuscript.

Funding

This analysis was supported by the Deutsche Krebshilfe (#109714).

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Authors and Affiliations

  1. Institute of Pathology, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625, Hannover, Germany

    Kais Hussein, Angelika Stucki-Koch & Hans Kreipe

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  1. Kais Hussein
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Contributions

Conception and design: K Hussein, H Kreipe.

Administrative support: H Kreipe.

Provision of study materials and patient data: K Hussein, H Kreipe, and A Stucki-Koch.

Collection and assembly of data: K Hussein and A Stucki-Koch.

Molecular analysis and immunohistochemistry: A Stucki-Koch and K Hussein.

Data analysis and interpretation: all authors.

Manuscript writing: K Hussein.

Final approval of manuscript: all authors.

Research design (KH, HK), laboratory work (KH, ASK), data analysis (KH, ASK), clinical data (KH), and writing of the paper (KH, ASK, HK).

Corresponding author

Correspondence to Kais Hussein.

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The authors declare that they have no conflicts of interest.

Ethical approval

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008. Statement of informed consent was not applicable since the manuscript does not contain any clinical study. The retrospective study of archived samples was approved by our local ethics committee (#758/10).

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Hussein, K., Stucki-Koch, A. & Kreipe, H. Profile of fibrosis-related gene transcripts and megakaryocytic changes in the bone marrow of myelodysplastic syndromes with fibrosis. Ann Hematol 97, 2099–2106 (2018). https://doi.org/10.1007/s00277-018-3411-9

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  • DOI: https://doi.org/10.1007/s00277-018-3411-9

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