Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

The bone-marrow niche in MDS and MGUS: implications for AML and MM

Nature Reviews Clinical Oncology volume 15, pages 219–233 (2018)Cite this article

Subjects

Key Points

  • Multiple myeloma is almost always preceded by monoclonal gammopathy of undetermined significance, and at least one-quarter of all patients with myelodysplastic syndromes (MDS) have disease that evolves into acute myeloid leukaemia; in turn, MDS are frequently anteceded by clonal haematopoiesis of indeterminate potential

  • The bone-marrow microenvironment has been recognized to be a vibrant and complex living tissue that can aid and abet neoplastic disease processes

  • Neoplastic clones can transform the local bone-marrow microenvironment to favour their own growth at the expense of nonmalignant haematopoietic cells

  • An intricate and dynamic relationship between stem cell 'seeds' and the niche 'soil' helps to determine whether healthy haematopoiesis or an overgrowth of haematological malignancies occurs within the bone marrow

  • Targeting microenvironment-specific alterations might not only prevent disease progression from precursor states but also enhance the effectiveness of available therapies for the overt malignancies once progression has occurred

Abstract

Several haematological malignancies, including multiple myeloma (MM) and acute myeloid leukaemia (AML), have well-defined precursor states that precede the development of overt cancer. MM is almost always preceded by monoclonal gammopathy of undetermined significance (MGUS), and at least a quarter of all patients with myelodysplastic syndromes (MDS) have disease that evolves into AML. In turn, MDS are frequently anteceded by clonal haematopoiesis of indeterminate potential (CHIP). The acquisition of additional genetic and epigenetic alterations over time clearly influences the increasingly unstable and aggressive behaviour of neoplastic haematopoietic clones; however, perturbations in the bone-marrow microenvironment are increasingly recognized to have key roles in initiating and supporting oncogenesis. In this Review, we focus on the concept that the haematopoietic neoplasia–microenvironment relationship is an intimate rapport between two partners, provide an overview of the evidence supporting a role for the bone-marrow niche in promoting neoplasia, and discuss the potential for niche-specific therapeutic targets.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Stem cell niches in normal bone marrow.
Figure 2: The components of the microenvironment in monoclonal gammopathy of undetermined significance and myelodysplastic syndrome.
Figure 3: Therapeutic agents that target the aberrant tumour microenvironment in multiple myeloma and myelodysplastic syndromes or acute myeloid leukaemia.

Similar content being viewed by others

References

  1. Schanz, J. et al. Coalesced multicentric analysis of 2,351 patients with myelodysplastic syndromes indicates an underestimation of poor-risk cytogenetics of myelodysplastic syndromes in the international prognostic scoring system. J. Clin. Oncol. 29, 1963–1970 (2011).

    PubMed  PubMed Central  Google Scholar 

  2. Papaemmanuil, E. et al. Clinical and biological implications of driver mutations in myelodysplastic syndromes. Blood 122, 3616–3627 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Greenberg, P. L. et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood 120, 2454–2465 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Steensma, D. P. et al. Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood 126, 9–16 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Jaiswal, S. et al. Age-related clonal hematopoiesis associated with adverse outcomes. N. Engl. J. Med. 371, 2488–2498 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Parker, J. E. et al. 'Low-risk' myelodysplastic syndrome is associated with excessive apoptosis and an increased ratio of pro- versus anti-apoptotic bcl-2-related proteins. Br. J. Haematol. 103, 1075–1082 (1998).

    CAS  PubMed  Google Scholar 

  7. Mittelman, M., Oster, H. S., Hoffman, M. & Neumann, D. The lower risk MDS patient at risk of rapid progression. Leuk. Res. 34, 1551–1555 (2010).

    PubMed  Google Scholar 

  8. Walter, M. J. et al. Clonal architecture of secondary acute myeloid leukemia. N. Engl. J. Med. 366, 1090–1098 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Enrico, A. et al. Influence of acute myeloid leukemia progression on the prognosis of 831 patients with myelodysplastic syndromes from the Argentine database. Clin. Lymphoma Myeloma Leuk. 743–752.e5 (2017).

  10. Østgård, L. S. et al. Epidemiology and clinical significance of secondary and therapy-related acute myeloid leukemia: a national population-based cohort study. J. Clin. Oncol. 33, 3641–3649 (2015).

    Google Scholar 

  11. Lindsley, R. C. et al. Acute myeloid leukemia ontogeny is defined by distinct somatic mutations. Blood 125, 1367–1376 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Landgren, O. et al. Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: a prospective study. Blood 113, 5412–5417 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Weiss, B. M., Abadie, J., Verma, P., Howard, R. S. & Kuehl, W. M. A monoclonal gammopathy precedes multiple myeloma in most patients. Blood 113, 5418–5422 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Landgren, O. Monoclonal gammopathy of undetermined significance and smoldering multiple myeloma: biological insights and early treatment strategies. Hematol. Am. Soc. Hematol. Educ. Program 2013, 478–487 (2013).

    Google Scholar 

  15. Kyle, R. A. & Rajkumar, S. V. Multiple myeloma. Blood 111, 2962–2972 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Rajkumar, S. V. Multiple myeloma: 2011 update on diagnosis, risk-stratification, and management. Am. J. Hematol. 86, 57–65 (2011).

    PubMed  Google Scholar 

  17. Lopez-Corral, L. et al. SNP-based mapping arrays reveal high genomic complexity in monoclonal gammopathies, from MGUS to myeloma status. Leukemia 26, 2521–2529 (2012).

    CAS  PubMed  Google Scholar 

  18. Cogle, C. R. et al. Bone marrow niche in the myelodysplastic syndromes. Leuk. Res. 39, 1020–1027 (2015).

    PubMed  Google Scholar 

  19. Bulycheva, E. et al. Myelodysplasia is in the niche: novel concepts and emerging therapies. Leukemia 29, 259–268 (2015).

    CAS  PubMed  Google Scholar 

  20. Calvi, L. M. & Link, D. C. The hematopoietic stem cell niche in homeostasis and disease. Blood 126, 2443–2451 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Mies, A., Bulycheva, E., Rogulj, I. M., Hofbauer, L. C. & Platzbecker, U. Alterations within the osteo-hematopoietic niche in MDS and their therapeutic implications. Curr. Pharm. Des. 22, 2323–2332 (2016).

    CAS  PubMed  Google Scholar 

  22. Raza, A., Cruz, R., Latif, T., Mukherjee, S. & Galili, N. The biology of myelodysplastic syndromes: unity despite heterogeneity. Hematol. Rep. 2, e4 (2010).

    PubMed  PubMed Central  Google Scholar 

  23. Roccaro, A. M. et al. BM mesenchymal stromal cell-derived exosomes facilitate multiple myeloma progression. J. Clin. Invest. 123, 1542–1555 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Moschetta, M. et al. Role of endothelial progenitor cells in cancer progression. Biochim. Biophys. Acta 1846, 26–39 (2014).

    CAS  PubMed  Google Scholar 

  25. Muz, B., de la Puente, P., Azab, F., Ghobrial, I. M. & Azab, A. K. Hypoxia promotes dissemination and colonization in new bone marrow niches in Waldenstrom's macroglobulinemia. Mol. Cancer Res. 13, 263–272 (2015).

    CAS  PubMed  Google Scholar 

  26. Reagan, M. R. et al. Investigating osteogenic differentiation in multiple myeloma using a novel 3D bone marrow niche model. Blood 124, 3250–3259 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Roccaro, A. M. et al. SDF-1 inhibition targets the bone marrow niche for cancer therapy. Cell Rep. 9, 118–128 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Zingone, A. et al. Altered cytokine and chemokine profiles in multiple myeloma and precursor disease. Cytokine 69, 294–297 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Kawano, Y. et al. Targeting the bone marrow microenvironment in multiple myeloma. Immunol. Rev. 263, 160–172 (2015).

    PubMed  Google Scholar 

  30. Roccaro, A. M. et al. CXCR4 regulates extra-medullary myeloma through epithelial-mesenchymal-transition-like transcriptional activation. Cell Rep. 12, 622–635 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Moschetta, M. et al. Targeting vasculogenesis to prevent progression in multiple myeloma. Leukemia 30, 1103–1115 (2016).

    CAS  PubMed  Google Scholar 

  32. Sacco, A. et al. Cancer cell dissemination and homing to the bone marrow in a zebrafish model. Cancer Res. 76, 463–471 (2016).

    CAS  PubMed  Google Scholar 

  33. Kawano, Y., Roccaro, A. M., Azzi, J. & Ghobrial, I. M. Multiple myeloma and the immune microenvironment. Curr. Cancer Drug Targets 17, 806–818 (2017).

    CAS  PubMed  Google Scholar 

  34. Das, R. et al. Microenvironment-dependent growth of preneoplastic and malignant plasma cells in humanized mice. Nat. Med. 22, 1351–1357 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Schepers, K., Campbell, T. B. & Passegue, E. Normal and leukemic stem cell niches: insights and therapeutic opportunities. Cell Stem Cell 16, 254–267 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Sperling, A. S., Gibson, C. J. & Ebert, B. L. The genetics of myelodysplastic syndrome: from clonal haematopoiesis to secondary leukaemia. Nat. Rev. Cancer 17, 5–19 (2017).

    CAS  PubMed  Google Scholar 

  37. Park, D., Sykes, D. B. & Scadden, D. T. The hematopoietic stem cell niche. Front. Biosci. 17, 30–39 (2012).

    CAS  Google Scholar 

  38. Papayannopoulou, T. & Scadden, D. T. Stem-cell ecology and stem cells in motion. Blood 111, 3923–3930 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Yu, V. W. & Scadden, D. T. Hematopoietic stem cell and its bone marrow niche. Curr. Top. Dev. Biol. 118, 21–44 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Kaplan, R. N. et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438, 820–827 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Valastyan, S. & Weinberg, R. A. Tumor metastasis: molecular insights and evolving paradigms. Cell 147, 275–292 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    CAS  PubMed  Google Scholar 

  43. Bhowmick, N. A. et al. TGF-beta signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia. Science 303, 848–851 (2004).

    CAS  PubMed  Google Scholar 

  44. Walkley, C. R., Shea, J. M., Sims, N. A., Purton, L. E. & Orkin, S. H. Rb regulates interactions between hematopoietic stem cells and their bone marrow microenvironment. Cell 129, 1081–1095 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Yang, F. C. et al. Nf1-dependent tumors require a microenvironment containing Nf1+/− and c-kit-dependent bone marrow. Cell 135, 437–448 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Raaijmakers, M. H. et al. Bone progenitor dysfunction induces myelodysplasia and secondary leukaemia. Nature 464, 852–857 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Kode, A. et al. Leukaemogenesis induced by an activating beta-catenin mutation in osteoblasts. Nature 506, 240–244 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Kode, A. et al. FoxO1-dependent induction of acute myeloid leukemia by osteoblasts in mice. Leukemia 30, 1–13 (2016).

    CAS  PubMed  Google Scholar 

  49. Roodman, G. D. Role of the bone marrow microenvironment in multiple myeloma. J. Bone Miner. Res. 17, 1921–1925 (2002).

    CAS  PubMed  Google Scholar 

  50. Podar, K., Richardson, P. G., Hideshima, T., Chauhan, D. & Anderson, K. C. The malignant clone and the bone-marrow environment. Best Pract. Res. Clin. Haematol. 20, 597–612 (2007).

    CAS  PubMed  Google Scholar 

  51. Podar, K., Hideshima, T., Chauhan, D. & Anderson, K. C. Targeting signalling pathways for the treatment of multiple myeloma. Expert Opin. Ther. Targets 9, 359–381 (2005).

    CAS  PubMed  Google Scholar 

  52. Podar, K., Chauhan, D. & Anderson, K. C. Bone marrow microenvironment and the identification of new targets for myeloma therapy. Leukemia 23, 10–24 (2009).

    CAS  PubMed  Google Scholar 

  53. Reagan, M. R. & Ghobrial, I. M. Multiple myeloma mesenchymal stem cells: characterization, origin, and tumor-promoting effects. Clin. Cancer Res. 18, 342–349 (2012).

    CAS  PubMed  Google Scholar 

  54. Manier, S. et al. Prognostic role of circulating exosomal miRNAs in multiple myeloma. Blood 129, 2429–2436 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Wang, J. & Xiao, Z. Mesenchymal stem cells in pathogenesis of myelodysplastic syndromes. Stem Cell. Investig. 1, 16 (2014).

    PubMed  PubMed Central  Google Scholar 

  56. Aanei, C. M. et al. Focal adhesion protein abnormalities in myelodysplastic mesenchymal stromal cells. Exp. Cell Res. 317, 2616–2629 (2011).

    CAS  PubMed  Google Scholar 

  57. Aanei, C. M. et al. Intrinsic growth deficiencies of mesenchymal stromal cells in myelodysplastic syndromes. Stem Cells Dev. 21, 1604–1615 (2012).

    CAS  PubMed  Google Scholar 

  58. Geyh, S. et al. Insufficient stromal support in MDS results from molecular and functional deficits of mesenchymal stromal cells. Leukemia 27, 1841–1851 (2013).

    CAS  PubMed  Google Scholar 

  59. Blau, O. et al. Mesenchymal stromal cells of myelodysplastic syndrome and acute myeloid leukemia patients have distinct genetic abnormalities compared with leukemic blasts. Blood 118, 5583–5592 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Blau, O. et al. Chromosomal aberrations in bone marrow mesenchymal stroma cells from patients with myelodysplastic syndrome and acute myeloblastic leukemia. Exp. Hematol. 35, 221–229 (2007).

    CAS  PubMed  Google Scholar 

  61. Oliveira, F. M. et al. Differential expression of AURKA and AURKB genes in bone marrow stromal mesenchymal cells of myelodysplastic syndrome: correlation with G-banding analysis and FISH. Exp. Hematol. 41, 198–208 (2013).

    PubMed  Google Scholar 

  62. Borojevic, R. et al. Bone marrow stroma in childhood myelodysplastic syndrome: composition, ability to sustain hematopoiesis in vitro, and altered gene expression. Leuk. Res 28, 831–844 (2004).

    CAS  PubMed  Google Scholar 

  63. Li, X. & Deeg, H. J. Murine xenogeneic models of myelodysplastic syndrome: an essential role for stroma cells. Exp. Hematol. 42, 4–10 (2014).

    CAS  PubMed  Google Scholar 

  64. Medyouf, H. et al. Myelodysplastic cells in patients reprogram mesenchymal stromal cells to establish a transplantable stem cell niche disease unit. Cell Stem Cell 14, 824–837 (2014).

    CAS  PubMed  Google Scholar 

  65. Todoerti, K. et al. Distinct transcriptional profiles characterize bone microenvironment mesenchymal cells rather than osteoblasts in relationship with multiple myeloma bone disease. Exp. Hematol. 38, 141–153 (2010).

    CAS  PubMed  Google Scholar 

  66. Garayoa, M. et al. Mesenchymal stem cells from multiple myeloma patients display distinct genomic profile as compared with those from normal donors. Leukemia 23, 1515–1527 (2009).

    CAS  PubMed  Google Scholar 

  67. Flores-Figueroa, E., Arana-Trejo, R. M., Gutiérrez-Espíndola, G., Pérez-Cabrera, A. & Mayani, H. Mesenchymal stem cells in myelodysplastic syndromes: phenotypic and cytogenetic characterization. Leuk. Res. 29, 215–224 (2005).

    CAS  PubMed  Google Scholar 

  68. Santamaria, C. et al. Impaired expression of DICER, DROSHA, SBDS and some microRNAs in mesenchymal stromal cells from myelodysplastic syndrome patients. Haematologica 97, 1218–1224 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Zambetti, N. A. et al. Mesenchymal inflammation drives genotoxic stress in hematopoietic stem cells and predicts disease evolution in human pre-leukemia. Cell Stem Cell 19, 613–627 (2016).

    CAS  PubMed  Google Scholar 

  70. Olechnowicz, S. W. & Edwards, C. M. Contributions of the host microenvironment to cancer-induced bone disease. Cancer Res. 74, 1625–1631 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Yavropoulou, M. P. & Yovos, J. G. The role of the Wnt signaling pathway in osteoblast commitment and differentiation. Hormones 6, 279–294 (2007).

    PubMed  Google Scholar 

  72. Roodman, G. D. Pathogenesis of myeloma bone disease. Leukemia 23, 435–441 (2009).

    CAS  PubMed  Google Scholar 

  73. Roodman, G. D. New potential targets for treating myeloma bone disease. Clin. Cancer Res. 12, 6270s–6273s (2006).

    CAS  PubMed  Google Scholar 

  74. Toscani, D., Bolzoni, M., Accardi, F., Aversa, F. & Giuliani, N. The osteoblastic niche in the context of multiple myeloma. Ann. NY Acad. Sci. 1335, 45–62 (2015).

    CAS  PubMed  Google Scholar 

  75. Bianchi, G. & Munshi, N. C. Pathogenesis beyond the cancer clone(s) in multiple myeloma. Blood 125, 3049–3058 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Huston, A. & Roodman, G. D. Role of the microenvironment in multiple myeloma bone disease. Future Oncol. 2, 371–378 (2006).

    PubMed  Google Scholar 

  77. Tripodo, C. et al. Stromal SPARC contributes to the detrimental fibrotic changes associated with myeloproliferation whereas its deficiency favors myeloid cell expansion. Blood 120, 3541–3554 (2012).

    CAS  PubMed  Google Scholar 

  78. Balderman, S. R. et al. Targeting of the bone marrow microenvironment improves outcome in a murine model of myelodysplastic syndrome. Blood 127, 616–625 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Kitagawa, M. et al. Overexpression of tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma by bone marrow cells from patients with myelodysplastic syndromes. Leukemia 11, 2049–2054 (1997).

    CAS  PubMed  Google Scholar 

  80. Wang, Z. et al. The different immunoregulatory functions on dendritic cells between mesenchymal stem cells derived from bone marrow of patients with low-risk or high-risk myelodysplastic syndromes. PLoS ONE 8, e57470 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Allampallam, K. et al. Biological significance of proliferation, apoptosis, cytokines, and monocyte/macrophage cells in bone marrow biopsies of 145 patients with myelodysplastic syndrome. Int. J. Hematol. 75, 289–297 (2002).

    CAS  PubMed  Google Scholar 

  82. Feng, X. et al. Cytokine signature profiles in acquired aplastic anemia and myelodysplastic syndromes. Haematologica 96, 602–606 (2011).

    CAS  PubMed  Google Scholar 

  83. Weiss, G. & Goodnough, L. T. Anemia of chronic disease. N. Engl. J. Med. 352, 1011–1023 (2005).

    CAS  PubMed  Google Scholar 

  84. Qiang, Y. W., Kopantzev, E. & Rudikoff, S. Insulinlike growth factor-I signaling in multiple myeloma: downstream elements, functional correlates, and pathway cross-talk. Blood 99, 4138–4146 (2002).

    CAS  PubMed  Google Scholar 

  85. Alsayed, Y. et al. Mechanisms of regulation of CXCR4/SDF-1 (CXCL12)-dependent migration and homing in multiple myeloma. Blood 109, 2708–2717 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Dankbar, B. et al. Vascular endothelial growth factor and interleukin-6 in paracrine tumor-stromal cell interactions in multiple myeloma. Blood 95, 2630–2636 (2000).

    CAS  PubMed  Google Scholar 

  87. Chauhan, D. et al. SHP2 mediates the protective effect of interleukin-6 against dexamethasone-induced apoptosis in multiple myeloma cells. J. Biol. Chem. 275, 27845–27850 (2000).

    CAS  PubMed  Google Scholar 

  88. Jacamo, R. et al. Reciprocal leukemia-stroma VCAM-1/VLA-4-dependent activation of NF-kappaB mediates chemoresistance. Blood 123, 2691–2702 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Quail, D. F. & Joyce, J. A. Microenvironmental regulation of tumor progression and metastasis. Nat. Med. 19, 1423–1437 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Swann, J. B. & Smyth, M. J. Immune surveillance of tumors. J. Clin. Invest. 117, 1137–1146 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Coulson-Thomas, V. J., Coulson-Thomas, Y. M., Gesteira, T. F. & Kao, W. W. Extrinsic and intrinsic mechanisms by which mesenchymal stem cells suppress the immune system. Ocul. Surf. 14, 121–134 (2016).

    PubMed  PubMed Central  Google Scholar 

  92. Uccelli, A. & de Rosbo, N. K. The immunomodulatory function of mesenchymal stem cells: mode of action and pathways. Ann. NY Acad. Sci. 1351, 114–126 (2015).

    PubMed  Google Scholar 

  93. Ghannam, S., Pene, J., Moquet-Torcy, G., Jorgensen, C. & Yssel, H. Mesenchymal stem cells inhibit human Th17 cell differentiation and function and induce a T regulatory cell phenotype. J. Immunol. 185, 302–312 (2010).

    CAS  PubMed  Google Scholar 

  94. Ghannam, S., Bouffi, C., Djouad, F., Jorgensen, C. & Noel, D. Immunosuppression by mesenchymal stem cells: mechanisms and clinical applications. Stem Cell Res. Ther. 1, 2 (2010).

    PubMed  PubMed Central  Google Scholar 

  95. Bettelli, E. et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441, 235–238 (2006).

    CAS  PubMed  Google Scholar 

  96. Noonan, K. et al. A novel role of IL-17-producing lymphocytes in mediating lytic bone disease in multiple myeloma. Blood 116, 3554–3563 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Feyler, S. et al. CD4+CD25+FoxP3+ regulatory T cells are increased whilst CD3+CD4−CD8−αβTCR+ double negative T cells are decreased in the peripheral blood of patients with multiple myeloma which correlates with disease burden. Br. J. Haematol. 144, 686–695 (2009).

    PubMed  Google Scholar 

  98. Zelle-Rieser, C. et al. T cells in multiple myeloma display features of exhaustion and senescence at the tumor site. J. Hematol. Oncol. 9, 116 (2016).

    PubMed  PubMed Central  Google Scholar 

  99. Giuliani, N. et al. Human myeloma cells stimulate the receptor activator of nuclear factor-kappa B ligand (RANKL) in T lymphocytes: a potential role in multiple myeloma bone disease. Blood 100, 4615–4621 (2002).

    CAS  PubMed  Google Scholar 

  100. Roussou, M. et al. Increased expression of macrophage inflammatory protein-1α on trephine biopsies correlates with extensive bone disease, increased angiogenesis and advanced stage in newly diagnosed patients with multiple myeloma. Leukemia 23, 2177–2181 (2009).

    CAS  PubMed  Google Scholar 

  101. Gorgun, G. T. et al. Tumor-promoting immune-suppressive myeloid-derived suppressor cells in the multiple myeloma microenvironment in humans. Blood 121, 2975–2987 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Gabrilovich, D. I. & Nagaraj, S. Myeloid-derived suppressor cells as regulators of the immune system. Nat. Rev. Immunol. 9, 162–174 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Kawano, Y. et al. Characterization of the role of regulatory T cells (Tregs) in inducing progression of multiple myeloma. Blood 126, 502 (2015).

    Google Scholar 

  104. Sallman, D. A., Cluzeau, T., Basiorka, A. A. & List, A. Unraveling the pathogenesis of MDS: the NLRP3 inflammasome and pyroptosis drive the MDS phenotype. Front. Oncol. 6, 151 (2016).

    PubMed  PubMed Central  Google Scholar 

  105. Basiorka, A. A. et al. The NLRP3 inflammasome functions as a driver of the myelodysplastic syndrome phenotype. Blood 128, 2960–2975 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Xin, J. et al. Necroptosis in spontaneously-mutated hematopoietic cells induces autoimmune bone marrow failure in mice. Haematologica 102, 295–307 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Tirosh, I. et al. Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq. Science 352, 189–196 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Testa, U., Labbaye, C., Castelli, G. & Pelosi, E. Oxidative stress and hypoxia in normal and leukemic stem cells. Exp. Hematol. 44, 540–560 (2016).

    CAS  PubMed  Google Scholar 

  109. Laukka, T. et al. Fumarate and succinate regulate expression of hypoxia-inducible genes via TET enzymes. J. Biol. Chem. 291, 4256–4265 (2016).

    CAS  PubMed  Google Scholar 

  110. Passaro, D. et al. Increased vascular permeability in the bone marrow microenvironment contributes to disease progression and drug response in acute myeloid leukemia. Cancer Cell 32, 324–341 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Teofili, L. et al. Endothelial progenitor cell dysfunction in myelodysplastic syndromes: possible contribution of a defective vascular niche to myelodysplasia. Neoplasia 17, 401–409 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Colla, S. et al. Low bone marrow oxygen tension and hypoxia-inducible factor-1α overexpression characterize patients with multiple myeloma: role on the transcriptional and proangiogenic profiles of CD138+ cells. Leukemia 24, 1967–1970 (2010).

    CAS  PubMed  Google Scholar 

  113. Azab, A. K. et al. Hypoxia promotes dissemination of multiple myeloma through acquisition of epithelial to mesenchymal transition-like features. Blood 119, 5782–5794 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Glavey, S. V. et al. Proteomic characterization of human multiple myeloma bone marrow extracellular matrix. Leukemia 31, 2426–2434 (2017).

    CAS  PubMed  Google Scholar 

  115. Yang, Y. et al. Soluble syndecan-1 promotes growth of myeloma tumors in vivo. Blood 100, 610–617 (2002).

    CAS  PubMed  Google Scholar 

  116. Foroushani, A. et al. Large-scale gene network analysis reveals the significance of extracellular matrix pathway and homeobox genes in acute myeloid leukemia: an introduction to the Pigengene package and its applications. BMC Med. Genom. 10, 16 (2017).

    Google Scholar 

  117. Mateos, M. V. et al. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N. Engl. J. Med. 369, 438–447 (2013).

    CAS  PubMed  Google Scholar 

  118. Zorat, F. et al. The clinical and biological effects of thalidomide in patients with myelodysplastic syndromes. Br. J. Haematol. 115, 881–894 (2001).

    CAS  PubMed  Google Scholar 

  119. Aguayo, A., Giles, F. & Albitar, M. Vascularity, angiogenesis and angiogenic factors in leukemias and myelodysplastic syndromes. Leuk. Lymphoma 44, 213–222 (2003).

    CAS  PubMed  Google Scholar 

  120. Ebert, B. L. et al. An erythroid differentiation signature predicts response to lenalidomide in myelodysplastic syndrome. PLoS Med. 5, e35 (2008).

    PubMed  PubMed Central  Google Scholar 

  121. Lu, L. et al. The anti-cancer drug lenalidomide inhibits angiogenesis and metastasis via multiple inhibitory effects on endothelial cell function in normoxic and hypoxic conditions. Microvasc. Res. 77, 78–86 (2009).

    CAS  PubMed  Google Scholar 

  122. Kronke, J. et al. Lenalidomide induces ubiquitination and degradation of CK1α in del(5q) MDS. Nature 523, 183–188 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Kronke, J. et al. Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science 343, 301–305 (2014).

    PubMed  Google Scholar 

  124. Oliva, E. N. et al. Lenalidomide in International Prognostic Scoring System Low and Intermediate-1 risk myelodysplastic syndromes with del(5q): an Italian phase II trial of health-related quality of life, safety and efficacy. Leuk. Lymphoma 54, 2458–2465 (2013).

    CAS  PubMed  Google Scholar 

  125. Wang, E. S. et al. A randomized, double-blind, placebo-controlled phase 2 study evaluating the efficacy and safety of romiplostim treatment of patients with low or intermediate-1 risk myelodysplastic syndrome receiving lenalidomide. J. Hematol. Oncol. 5, 71 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Swami, A. et al. Engineered nanomedicine for myeloma and bone microenvironment targeting. Proc. Natl Acad. Sci. USA 111, 10287–10292 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Rajkumar, S. V. & Kyle, R. A. Angiogenesis in multiple myeloma. Semin. Oncol. 28, 560–564 (2001).

    CAS  PubMed  Google Scholar 

  128. Palumbo, A. et al. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N. Engl. J. Med. 375, 754–766 (2016).

    CAS  PubMed  Google Scholar 

  129. Dimopoulos, M. A. et al. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N. Engl. J. Med. 375, 1319–1331 (2016).

    CAS  PubMed  Google Scholar 

  130. Lonial, S. et al. Elotuzumab therapy for relapsed or refractory multiple myeloma. N. Engl. J. Med. 373, 621–631 (2015).

    CAS  PubMed  Google Scholar 

  131. Ansell, S. M. et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. N. Engl. J. Med. 372, 311–319 (2015).

    PubMed  Google Scholar 

  132. Topalian, S. L. et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 366, 2443–2454 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Akbay, E. A. et al. Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors. Cancer Discov. 3, 1355–1363 (2013).

    CAS  PubMed  Google Scholar 

  134. Benson, D. M. Jr et al. The PD-1/PD-L1 axis modulates the natural killer cell versus multiple myeloma effect: a therapeutic target for CT-011, a novel monoclonal anti-PD-1 antibody. Blood 116, 2286–2294 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Rosenblatt, J. et al. PD-1 blockade by CT-011, anti-PD-1 antibody, enhances ex vivo T-cell responses to autologous dendritic cell/myeloma fusion vaccine. J. Immunother. 34, 409–418 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Atanackovic, D., Luetkens, T. & Kroger, N. Coinhibitory molecule PD-1 as a potential target for the immunotherapy of multiple myeloma. Leukemia 28, 993–1000 (2014).

    CAS  PubMed  Google Scholar 

  137. Badros, A. et al. Pembrolizumab, pomalidomide, and low-dose dexamethasone for relapsed/refractory multiple myeloma. Blood 130, 1189–1197 (2017).

    CAS  PubMed  Google Scholar 

  138. Ayed, A. O., Chang, L. J. & Moreb, J. S. Immunotherapy for multiple myeloma: current status and future directions. Crit. Rev. Oncol. Hematol. 96, 399–412 (2015).

    PubMed  Google Scholar 

  139. Cheah, C. Y., Fowler, N. H. & Neelapu, S. S. Targeting the programmed death-1/programmed death-ligand 1 axis in lymphoma. Curr. Opin. Oncol. 27, 384–391 (2015).

    CAS  PubMed  Google Scholar 

  140. Jelinek, T. & Hajek, R. PD-1/PD-L1 inhibitors in multiple myeloma: the present and the future. Oncoimmunology 5, e1254856 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. [No authors listed] FDA alerts healthcare professionals and oncology clinical investigators about two clinical trials on hold evaluating KEYTRUDA® (pembrolizumab) in patients with multiple myeloma. US Food and Drug Administration https://www.fda.gov/Drugs/DrugSafety/ucm574305.htm (2017).

  142. Agazzi, A. Report on the 56th ASH Annual Meeting, San Francisco, 4–9 December 2014. ecancermedicalscience 9, 514 (2015).

    PubMed  PubMed Central  Google Scholar 

  143. Atanackovic, D., Radhakrishnan, S. V., Bhardwaj, N. & Luetkens, T. Chimeric antigen receptor (CAR) therapy for multiple myeloma. Br. J. Haematol. 172, 685–698 (2016).

    PubMed  Google Scholar 

  144. Abe-Suzuki, S. et al. CXCL12+ stromal cells as bone marrow niche for CD34+ hematopoietic cells and their association with disease progression in myelodysplastic syndromes. Lab. Invest. 94, 1212–1223 (2014).

    CAS  PubMed  Google Scholar 

  145. Zhang, Y. et al. SDF-1/CXCR4 axis in myelodysplastic syndromes: correlation with angiogenesis and apoptosis. Leuk. Res. 36, 281–286 (2012).

    CAS  PubMed  Google Scholar 

  146. Sison, E. A., McIntyre, E., Magoon, D. & Brown, P. Dynamic chemotherapy-induced upregulation of CXCR4 expression: a mechanism of therapeutic resistance in pediatric AML. Mol. Cancer Res. 11, 1004–1016 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Ludwig, H. et al. Olaptesed pegol, an anti-CXCL12/SDF-1 Spiegelmer, alone and with bortezomib dexamethasone in relapsed/refractory multiple myeloma: a phase IIa study. Leukemia 31, 997–1000 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Uy, G. L. et al. A phase 1/2 study of chemosensitization with the CXCR4 antagonist plerixafor in relapsed or refractory acute myeloid leukemia. Blood 119, 3917–3924 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Morgan, G. J. et al. Effects of zoledronic acid versus clodronic acid on skeletal morbidity in patients with newly diagnosed multiple myeloma (MRC Myeloma IX): secondary outcomes from a randomised controlled trial. Lancet Oncol. 12, 743–752 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. D'Arena, G. et al. Pamidronate versus observation in asymptomatic myeloma: final results with long-term follow-up of a randomized study. Leuk. Lymphoma 52, 771–775 (2011).

    CAS  PubMed  Google Scholar 

  151. Dong, M. et al. Phase III clinical study of zoledronic acid in the treatment of pain induced by bone metastasis from solid tumor or multiple myeloma [Chinese]. Zhonghua Zhong Liu Za Zhi 30, 215–220 (2008).

    CAS  PubMed  Google Scholar 

  152. Rosen, L. S. et al. Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: a randomized, double-blind, multicenter, comparative trial. Cancer 98, 1735–1744 (2003).

    CAS  PubMed  Google Scholar 

  153. Musto, P. et al. Pamidronate reduces skeletal events but does not improve progression-free survival in early-stage untreated myeloma: results of a randomized trial. Leuk. Lymphoma 44, 1545–1548 (2003).

    CAS  PubMed  Google Scholar 

  154. Iyer, S. P. et al. A phase IB multicentre dose-determination study of BHQ880 in combination with anti-myeloma therapy and zoledronic acid in patients with relapsed or refractory multiple myeloma and prior skeletal-related events. Br. J. Haematol. 167, 366–375 (2014).

    CAS  PubMed  Google Scholar 

  155. Qian, J. et al. Dickkopf-1 (DKK1) is a widely expressed and potent tumor-associated antigen in multiple myeloma. Blood 110, 1587–1594 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Vij, R. et al. An open-label, phase 2 trial of denosumab in the treatment of relapsed or plateau-phase multiple myeloma. Am. J. Hematol. 84, 650–656 (2009).

    CAS  PubMed  Google Scholar 

  157. Ghobrial, I. M. & Landgren, O. How I treat smoldering multiple myeloma. Blood 124, 3380–3388 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  158. Stasi, R. & Amadori, S. Infliximab chimaeric anti-tumour necrosis factor alpha monoclonal antibody treatment for patients with myelodysplastic syndromes. Br. J. Haematol. 116, 334–337 (2002).

    CAS  PubMed  Google Scholar 

  159. Scott, B. L. et al. Anti-thymocyte globulin plus etanercept as therapy for myelodysplastic syndromes (MDS): a phase II study. Br. J. Haematol. 149, 706–710 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Scott, B. L. et al. Prolonged responses in patients with MDS and CMML treated with azacitidine and etanercept. Br. J. Haematol. 148, 944–947 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Garcia-Manero, G. et al. A phase 2, randomized, double-blind, multicenter study comparing siltuximab plus best supportive care (BSC) with placebo plus BSC in anemic patients with International Prognostic Scoring System low- or intermediate-1-risk myelodysplastic syndrome. Am. J. Hematol. 89, E156–E162 (2014).

    CAS  PubMed  Google Scholar 

  162. Magarotto, V., Salvini, M., Bonello, F., Bringhen, S. & Palumbo, A. Strategy for the treatment of multiple myeloma utilizing monoclonal antibodies: a new era begins. Leuk. Lymphoma 57, 537–556 (2016).

    CAS  PubMed  Google Scholar 

  163. Orlowski, R. Z. et al. A phase 2, randomized, double-blind, placebo-controlled study of siltuximab (anti-IL-6 mAb) and bortezomib versus bortezomib alone in patients with relapsed or refractory multiple myeloma. Am. J. Hematol. 90, 42–49 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. Shah, J. J. et al. Siltuximab (CNTO 328) with lenalidomide, bortezomib and dexamethasone in newly-diagnosed, previously untreated multiple myeloma: an open-label phase I trial. Blood Cancer J. 6, e396 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  165. van Rhee, F. et al. A phase 2, open-label, multicenter study of the long-term safety of siltuximab (an anti-interleukin-6 monoclonal antibody) in patients with multicentric Castleman disease. Oncotarget 6, 30408–30419 (2015).

    PubMed  PubMed Central  Google Scholar 

  166. Carrancio, S. et al. An activin receptor IIA ligand trap promotes erythropoiesis resulting in a rapid induction of red blood cells and haemoglobin. Br. J. Haematol. 165, 870–882 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. Giagounidis, A. et al. Luspatercept treatment leads to long term increases in hemoglobin and reductions in transfusion burden in patients with low or intermediate-1 risk myelodysplastic syndromes (MDS): preliminary results from the phase 2 PACE-MDS extension study. Blood 126, 92 (2015).

    Google Scholar 

  168. Dussiot, M. et al. An activin receptor IIA ligand trap corrects ineffective erythropoiesis in beta-thalassemia. Nat. Med. 20, 398–407 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  169. Mies, A. & Platzbecker, U. Increasing the effectiveness of hematopoiesis in myelodysplastic syndromes: erythropoiesis-stimulating agents and transforming growth factor-beta superfamily inhibitors. Semin. Hematol. 54, 141–146 (2017).

    PubMed  Google Scholar 

  170. McMillin, D. W. et al. Tumor cell-specific bioluminescence platform to identify stroma-induced changes to anticancer drug activity. Nat. Med. 16, 483–489 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Straussman, R. et al. Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature 487, 500–504 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  172. Yaccoby, S. et al. Myeloma interacts with the bone marrow microenvironment to induce osteoclastogenesis and is dependent on osteoclast activity. Br. J. Haematol. 116, 278–290 (2002).

    PubMed  Google Scholar 

  173. Wang, J. et al. Bone marrow stromal cell-derived exosomes as communicators in drug resistance in multiple myeloma cells. Blood 124, 555–566 (2014).

    CAS  PubMed  Google Scholar 

  174. Tai, Y. T. et al. CRM1 inhibition induces tumor cell cytotoxicity and impairs osteoclastogenesis in multiple myeloma: molecular mechanisms and therapeutic implications. Leukemia 28, 155–165 (2014).

    CAS  PubMed  Google Scholar 

  175. Roccaro, M. et al. Stroma-derived exosomes mediate oncogenesis in multiple myeloma Blood 118, 625 (2011).

    Google Scholar 

  176. Maiso, P. et al. Metabolic signature identifies novel targets for drug resistance in multiple myeloma. Cancer Res. 75, 2071–2082 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. Hu, J. et al. Targeting the multiple myeloma hypoxic niche with TH-302, a hypoxia-activated prodrug. Blood 116, 1524–1527 (2010).

    CAS  PubMed  Google Scholar 

  178. Laubach, J. et al. Preliminary safety and efficacy of TH-302, an investigational hypoxia-activated prodrug, combined with bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma (RR MM) [abstract]. J. Clin. Oncol. 32 (Suppl.), 8534 (2014).

    Google Scholar 

  179. Bajaj, J. et al. CD98-mediated adhesive signaling enables the establishment and propagation of acute myelogenous leukemia. Cancer Cell 30, 792–805 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. Carter, B. Z. et al. Anti-apoptotic ARC protein confers chemoresistance by controlling leukemia-microenvironment interactions through a NFκB/IL1β signaling network. Oncotarget 7, 20054–20067 (2016).

    PubMed  PubMed Central  Google Scholar 

  181. Stone, R. M. et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N. Engl. J. Med. 377, 454–464 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  182. Ghiaur, G. & Levis, M. Mechanisms of Resistance to FLT3 Inhibitors and the Role of the Bone Marrow Microenvironment. Hematol. Oncol. Clin. North Am. 31, 681–692 (2017).

    PubMed  PubMed Central  Google Scholar 

  183. Verstovsek, S. et al. Clinical relevance of vascular endothelial growth factor receptors 1 and 2 in acute myeloid leukaemia and myelodysplastic syndrome. Br. J. Haematol. 118, 151–156 (2002).

    CAS  PubMed  Google Scholar 

  184. Hu, Q. et al. Soluble vascular endothelial growth factor receptor 1, and not receptor 2, is an independent prognostic factor in acute myeloid leukemia and myelodysplastic syndromes. Cancer 100, 1884–1891 (2004).

    CAS  PubMed  Google Scholar 

  185. Verburgh, E. et al. Additional prognostic value of bone marrow histology in patients subclassified according to the International Prognostic Scoring System for myelodysplastic syndromes. J. Clin. Oncol. 21, 273–282 (2003).

    CAS  PubMed  Google Scholar 

  186. Stoddart, A. et al. Inhibition of WNT signaling in the bone marrow niche prevents the development of MDS in the Apcdel/+ MDS mouse model. Blood 129, 2959–2970 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  187. Shastri, A., Will, B., Steidl, U. & Verma, A. Stem and progenitor cell alterations in myelodysplastic syndromes. Blood 129, 1586–1594 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  188. Chen, X. et al. Induction of myelodysplasia by myeloid-derived suppressor cells. J. Clin. Invest. 123, 4595–4611 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  189. Chauhan, D. et al. Functional interaction of plasmacytoid dendritic cells with multiple myeloma cells: a therapeutic target. Cancer Cell 16, 309–323 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  190. Ray, A. et al. A novel agent SL-401 induces anti-myeloma activity by targeting plasmacytoid dendritic cells, osteoclastogenesis and cancer stem-like cells. Leukemia 31, 2652–2660 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  191. Vercauteren, S. M. et al. T cells of patients with myelodysplastic syndrome are frequently derived from the malignant clone. Br. J. Haematol. 156, 409–412 (2012).

    PubMed  PubMed Central  Google Scholar 

  192. Epling-Burnette, P. K. et al. Prevalence and clinical association of clonal T-cell expansions in myelodysplastic syndrome. Leukemia 21, 659–667 (2007).

    CAS  PubMed  Google Scholar 

  193. Singhal, S. et al. Antitumor activity of thalidomide in refractory multiple myeloma. N. Engl. J. Med. 341, 1565–1571 (1999).

    CAS  PubMed  Google Scholar 

  194. Weber, D. et al. Lenalidomide plus high-dose dexamethasone provides improved overall survival compared to high-dose dexamethasone alone for relapsed or refractory multiple myeloma (MM): results of a North American phase III study (MM-009) [abstract]. J. Clin. Oncol. 24, (Suppl.), 7521 (2006).

    Google Scholar 

  195. Dimopoulos, M. et al. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N. Engl. J. Med. 357, 2123–2132 (2007).

    CAS  PubMed  Google Scholar 

  196. Lonial, S. et al. Elotuzumab in combination with lenalidomide and low-dose dexamethasone in relapsed or refractory multiple myeloma. J. Clin. Oncol. 30, 1953–1959 (2012).

    CAS  PubMed  Google Scholar 

  197. Lesokhin, A. A. et al. Preliminary results of a phase I study of nivolumab (BMS-936558) in patients with relapsed or refractory lymphoid malignancies. Blood 124, 291 (2014).

    Google Scholar 

  198. Sidaway, P. Haematological cancer: Pembrolizumab is effective in multiple myeloma. Nat. Rev. Clin. Oncol. 14, 393 (2017).

    PubMed  Google Scholar 

  199. Davids, M. S. et al. Ipilimumab for patients with relapse after allogeneic transplantation. N. Engl. J. Med. 375, 143–153 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  200. Noonan, K. A. et al. Adoptive transfer of activated marrow-infiltrating lymphocytes induces measurable antitumor immunity in the bone marrow in multiple myeloma. Sci. Transl Med. 7, 288ra78 (2015).

    PubMed  PubMed Central  Google Scholar 

  201. Pyzer, A. R., Avigan, D. E. & Rosenblatt, J. Clinical trials of dendritic cell-based cancer vaccines in hematologic malignancies. Hum. Vaccin. Immunother. 10, 3125–3131 (2014).

    PubMed  Google Scholar 

  202. Rosenblatt, J. et al. Vaccination with dendritic cell/tumor fusions following autologous stem cell transplant induces immunologic and clinical responses in multiple myeloma patients. Clin. Cancer Res. 19, 3640–3648 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  203. Ghobrial, I. et al. Phase I trial of plerixafor and bortezomib as a chemosensitization strategy in relapsed or relapsed/refractory multiple myeloma. Blood 118, 1874 (2011).

    Google Scholar 

Download references

Acknowledgements

I.M.G. acknowledges research funding from the US Department of Health & Human Services, National Institutes of Health, Center for Scientific Review (PQ1 grant 1R01CA205954-01). Editorial assistance was provided by Helen Pickersgil at Lifescience.

Author information

Authors and Affiliations

  1. Division of Hematological Malignancies, Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, 02115, Massachusetts, USA

    Irene M. Ghobrial, Alexandre Detappe, Kenneth C. Anderson & David P. Steensma

Authors
  1. Irene M. Ghobrial
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alexandre Detappe
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kenneth C. Anderson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. David P. Steensma
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors researched data, wrote, and reviewed and/or edited the manuscript before submission. Additionally, I.M.G., K.C.A, and D.P.S. made substantial contributions to discussion of content.

Corresponding authors

Correspondence to Irene M. Ghobrial or David P. Steensma.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ghobrial, I., Detappe, A., Anderson, K. et al. The bone-marrow niche in MDS and MGUS: implications for AML and MM. Nat Rev Clin Oncol 15, 219–233 (2018). https://doi.org/10.1038/nrclinonc.2017.197

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrclinonc.2017.197

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer