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Stem cell biology

Functional inhibition of mesenchymal stromal cells in acute myeloid leukemia

Leukemia volume 30, pages 683–691 (2016)Cite this article

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Abstract

Hematopoietic insufficiency is the hallmark of acute myeloid leukemia (AML) and predisposes patients to life-threatening complications such as bleeding and infections. Addressing the contribution of mesenchymal stromal cells (MSC) to AML-induced hematopoietic failure we show that MSC from AML patients (n=64) exhibit significant growth deficiency and impaired osteogenic differentiation capacity. This was molecularly reflected by a specific methylation signature affecting pathways involved in cell differentiation, proliferation and skeletal development. In addition, we found distinct alterations of hematopoiesis-regulating factors such as Kit-ligand and Jagged1 accompanied by a significantly diminished ability to support CD34+ hematopoietic stem and progenitor cells in long-term culture-initiating cells (LTC-ICs) assays. This deficient osteogenic differentiation and insufficient stromal support was reversible and correlated with disease status as indicated by Osteocalcin serum levels and LTC-IC frequencies returning to normal values at remission. In line with this, cultivation of healthy MSC in conditioned medium from four AML cell lines resulted in decreased proliferation and osteogenic differentiation. Taken together, AML-derived MSC are molecularly and functionally altered and contribute to hematopoietic insufficiency. Inverse correlation with disease status and adoption of an AML-like phenotype after exposure to leukemic conditions suggests an instructive role of leukemic cells on bone marrow microenvironment.

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References

  1. Lichtman MA . Interrupting the inhibiton of normal hematopoiesis in myelogenous leukemia: a hypothetical approach to therapy. Stem Cells 2000; 18: 304–306.

    Article  CAS  PubMed  Google Scholar 

  2. Frenette PS, Pinho S, Lucas D, Scheiermann C . Mesenchymal stem cell: keystone of the hematopoietic stem cell niche and a stepping-stone for regenerative medicine. Annu Rev Immunol 2013; 31: 285–316.

    Article  PubMed  Google Scholar 

  3. 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 

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

    Article  CAS  PubMed  Google Scholar 

  5. Jacamo R, Chen Y, Wang Z, Ma W, Zhang M, Spaeth EL et al. Reciprocal leukemia-stroma VCAM-1/VLA-4-dependent activation of NF-kappaB mediates chemoresistance. Blood 2014; 123: 2691–2702.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Jin L, Hope KJ, Zhai Q, Smadja-Joffe F, Dick JE . Targeting of CD44 eradicates human acute myeloid leukemic stem cells. Nat Med 2006; 12: 1167–1174.

    Article  PubMed  Google Scholar 

  7. Matsunaga T, Takemoto N, Sato T, Takimoto R, Tanaka I, Fujimi A et al. Interaction between leukemic-cell VLA-4 and stromal fibronectin is a decisive factor for minimal residual disease of acute myelogenous leukemia. Nat Med 2003; 9: 1158–1165.

    Article  CAS  PubMed  Google Scholar 

  8. Zeng Z, Shi YX, Samudio IJ, Wang RY, Ling X, Frolova O et al. Targeting the leukemia microenvironment by CXCR4 inhibition overcomes resistance to kinase inhibitors and chemotherapy in AML. Blood 2009; 113: 6215–6224.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Kode A, Manavalan JS, Mosialou I, Bhagat G, Rathinam CV, Luo N et al. Leukaemogenesis induced by an activating beta-catenin mutation in osteoblasts. Nature 2014; 506: 240–244.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. 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 

  11. 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 

  12. Krevvata M, Silva BC, Manavalan JS, Galan-Diez M, Kode A, Matthews BG et al. Inhibition of leukemia cell engraftment and disease progression in mice by osteoblasts. Blood 2014; 124: 2834–2846.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Hanoun M, Zhang D, Mizoguchi T, Pinho S, Pierce H, Kunisaki Y et al. Acute myelogenous leukemia-induced sympathetic neuropathy promotes malignancy in an altered hematopoietic stem cell niche. Cell Stem Cell 2014; 15: 365–375.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. 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 

  15. Geyh S, Oz S, Cadeddu RP, Frobel J, Bruckner B, Kundgen A et al. Insufficient stromal support in MDS results from molecular and functional deficits of mesenchymal stromal cells. Leukemia 2013; 27: 1841–1851.

    Article  CAS  PubMed  Google Scholar 

  16. 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 

  17. 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 

  18. 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 

  19. 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 

  20. 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 

  21. 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 

  22. Platzbecker U, Germing U, Giagounidis A, Goetze K, Kiewe P, Mayer K et al. ACE-536 increases hemoglobin and reduces transfusion burden in patients with low or intermediate-1 risk myelodysplastic syndromes (MDS): preliminary results from a phase 2 study. Blood 2014; 124: 411.

    Google Scholar 

  23. Mendelson A, Frenette PS . Hematopoietic stem cell niche maintenance during homeostasis and regeneration. Nat Med 2014; 20: 833–846.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Kim JA, Shim JS, Lee GY, Yim HW, Kim TM, Kim M et al. Microenvironmental remodeling as a parameter and prognostic factor of heterogeneous leukemogenesis in acute myelogenous leukemia. Cancer Res 2015; 75: 2222–2231.

    Article  CAS  PubMed  Google Scholar 

  25. Huan J, Hornick NI, Goloviznina NA, Kamimae-Lanning AN, David LL, Wilmarth PA et al. Coordinate regulation of residual bone marrow function by paracrine trafficking of AML exosomes. Leukemia 2015; 29: 2285–2295.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Chandran P, Le Y, Li Y, Sabloff M, Mehic J, Rosu-Myles M et al. Mesenchymal stromal cells from patients with acute myeloid leukemia have altered capacity to expand differentiated hematopoietic progenitors. Leuk Res 2015; 39: 486–493.

    Article  CAS  PubMed  Google Scholar 

  27. Chen Q, Yuan Y, Chen T . Morphology, differentiation and adhesion molecule expression changes of bone marrow mesenchymal stem cells from acute myeloid leukemia patients. Mol Med Rep 2014; 9: 293–298.

    Article  CAS  PubMed  Google Scholar 

  28. Zhao ZG, Liang Y, Li K, Li WM, Li QB, Chen ZC et al. Phenotypic and functional comparison of mesenchymal stem cells derived from the bone marrow of normal adults and patients with hematologic malignant diseases. Stem Cells Dev 2007; 16: 637–648.

    Article  CAS  PubMed  Google Scholar 

  29. Hayashi M, Maeda S, Aburatani H, Kitamura K, Miyoshi H, Miyazono K et al. Pitx2 prevents osteoblastic transdifferentiation of myoblasts by bone morphogenetic proteins. J Biol Chem 2008; 283: 565–571.

    Article  CAS  PubMed  Google Scholar 

  30. 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 

  31. Kim YW, Koo BK, Jeong HW, Yoon MJ, Song R, Shin J et al. Defective Notch activation in microenvironment leads to myeloproliferative disease. Blood 2008; 112: 4628–4638.

    Article  CAS  PubMed  Google Scholar 

  32. Walkley CR, Olsen GH, Dworkin S, Fabb SA, Swann J, McArthur GA et al. A microenvironment-induced myeloproliferative syndrome caused by retinoic acid receptor gamma deficiency. Cell 2007; 129: 1097–1110.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wang L, Zhang H, Rodriguez S, Cao L, Parish J, Mumaw C et al. Notch-dependent repression of miR-155 in the bone marrow niche regulates hematopoiesis in an NF-kappaB-dependent manner. Cell Stem Cell 2014; 15: 51–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Blank U, Karlsson S . TGF-beta signaling in the control of hematopoietic stem cells. Blood 2015; 125: 3542–3550.

    Article  CAS  PubMed  Google Scholar 

  35. Suragani RN, Cadena SM, Cawley SM, Sako D, Mitchell D, Li R et al. Transforming growth factor-beta superfamily ligand trap ACE-536 corrects anemia by promoting late-stage erythropoiesis. Nat Med 2014; 20: 408–414.

    Article  CAS  PubMed  Google Scholar 

  36. Colmone A, Amorim M, Pontier AL, Wang S, Jablonski E, Sipkins DA . Leukemic cells create bone marrow niches that disrupt the behavior of normal hematopoietic progenitor cells. Science 2008; 322: 1861–1865.

    Article  CAS  PubMed  Google Scholar 

  37. Miraki-Moud F, Anjos-Afonso F, Hodby KA, Griessinger E, Rosignoli G, Lillington D et al. Acute myeloid leukemia does not deplete normal hematopoietic stem cells but induces cytopenias by impeding their differentiation. Proc Natl Acad Sci USA 2013; 110: 13576–13581.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by the Leukämie Lymphom Liga e. V., Duesseldorf, Germany. We would like to thank Katharina Raba and Johannes Fischer for excellent technical assistance, as well as Günter Raddatz for his bioinformatics support and advice. This work was also supported by a research grant of the Deutsche Forschungsgemeinschaft (to TS, SCHR 1470/1-1).

Author contributions

Conception and design: TS, RH, FL, SG and MR-P. Provision of patients’ samples: UG, CZ, GK, RF and TS. Experiments, collection and assembly of data: SG, TS, PJ, R-PC, MR-P, CMW and DH. Data analysis and interpretation: TS, RH, SG, UG, FL, MR-P, JG, R-PC, CK and PJGK. Manuscript writing: TS, SG, RH, FL and MR-P. Final approval of the manuscript: all authors.

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Authors and Affiliations

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

    S Geyh, P Jäger, R-P Cadeddu, C M Wilk, R Fenk, U Germing, G Kobbe, R Haas & T Schroeder

  2. University Tumor Center Duesseldorf, University of Duesseldorf, Medical Faculty, Duesseldorf, Germany

    S Geyh & M Rodríguez-Paredes

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

    M Rodríguez-Paredes, J Gutekunst & F Lyko

  4. Department of Hematology, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany

    C Khandanpour

  5. Division of Hematology, University Hospital Zurich and University of Zurich, Zurich, Switzerland

    C M Wilk

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

    C Zilkens

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

    D Hermsen

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  1. S Geyh
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Correspondence to T Schroeder.

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The authors declare no conflict of interest.

Additional information

Parts of this study have been presented at the 56th American Society of Hematology (ASH) Annual Meeting, San Francisco, CA, December 2014 and at the Annual Meeting of the German–Austrian–Suisse Society of Hematology and Oncology (DGHO), Hamburg, Germany, October 2014.

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Geyh, S., Rodríguez-Paredes, M., Jäger, P. et al. Functional inhibition of mesenchymal stromal cells in acute myeloid leukemia. Leukemia 30, 683–691 (2016). https://doi.org/10.1038/leu.2015.325

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