In the setting of hematological neoplasms, changes in the bone marrow (BM) stroma might arise from pressure exerted by the neoplastic clone in shaping a supportive microenvironment, or from chronic perturbation of the BM homeostasis. Under such conditions, alterations in the composition of the BM stroma can be profound, and could emerge as relevant prognostic factors. In this Review, we delineate the multifaceted contribution of the BM stroma to the pathobiology of several hematological neoplasms, and discuss the impact of stromal modifications on the natural course of these diseases. Specifically, we highlight the involvement of BM stromal components in lymphoid and myeloid malignancies, and present the most relevant processes responsible for remodeling the BM stroma. The role of bystander BM stromal elements in the setting of hematological neoplasms is discussed, strengthening the rationale for treatment strategies that target the BM stroma.
BM stromal changes in lymphoid malignancies are engendered by neoplastic cells to support their localization, proliferation and survival, and to suppress effective antitumor immune responses
Lymphoid neoplastic clones are able to manipulate the BM environment either directly, or through the co-optation of accessory cells such as macrophages and mast cells
Treatment strategies interfering with the axes involved in crosstalk between neoplastic cells and BM stroma may prove effective in lymphoid malignancies, when combined with therapies that target the neoplastic clones
Stromal alterations associated with myeloid malignancies, such as BM fibrosis, could be profound and negatively influence the clinical course of the disease and response to therapy
Drugs that could potentially control the proliferation of BM stromal components, such as tyrosine kinase inhibitors, proteasome inhibitors, and immunomodulatory agents are promising for the treatment of myeloid malignancies
Subscribe to Journal
Get full journal access for 1 year
only $17.42 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Xie, Y. et al. Detection of functional haematopoietic stem cell niche using real-time imaging. Nature 457, 97–101 (2009).
Wilson, A. & Trumpp, A. Bone-marrow haematopoietic-stem-cell niches. Nat. Rev. Immunol. 6, 93–106 (2006).
Ribatti, D. Bone marrow vascular niche and the control of tumor growth in hematological malignancies. Leukemia 24, 1247–1248 (2010).
Sugiyama, T., Kohara, H., Noda, M. & Nagasawa, T. Maintenance of the hematopoietic stem cell pool by CXCL12-CXCR4 chemokine signaling in bone marrow stromal cell niches. Immunity 25, 977–988 (2006).
Blank, U., Karlsson, G. & Karlsson, S. Signaling pathways governing stem-cell fate. Blood 111, 492–503 (2008).
Grabher, C., von Boehmer, H. & Look, A. T. Notch 1 activation in the molecular pathogenesis of T-cell acute lymphoblastic leukaemia. Nat. Rev. Cancer 6, 347–359 (2006).
Hadland, B. K. et al. A requirement for Notch1 distinguishes 2 phases of definitive hematopoiesis during development. Blood 104, 3097–3105 (2004).
Torlakovic, E., Tenstad, E., Funderud, S. & Rian, E. CD10+ stromal cells form B-lymphocyte maturation niches in the human bone marrow. J. Pathol. 205, 311–317 (2005).
Méndez-Ferrer, S. et al. Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature 466, 829–834 (2010).
Wei, J. et al. Microenvironment determines lineage fate in a human model of MLL-AF9 leukemia. Cancer Cell 13, 483–495 (2008).
Naveiras, O. et al. Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment. Nature 460, 259–263 (2009).
Mesa, R. A., Hanson, C. A., Rajkumar, S. V., Schroeder, G. & Tefferi, A. Evaluation and clinical correlations of bone marrow angiogenesis in myelofibrosis with myeloid metaplasia. Blood 96, 3374–3380 (2000).
Thiele, J. & Kvasnicka, H. M. Grade of bone marrow fibrosis is associated with relevant hematological findings—a clinicopathological study on 865 patients with chronic idiopathic myelofibrosis. Ann. Hematol. 85, 226–232 (2006).
Vener, C. et al. Prognostic implications of the European consensus for grading of bone marrow fibrosis in chronic idiopathic myelofibrosis. Blood 111, 1862–1865 (2008).
Della Porta, M. G. et al. Clinical relevance of bone marrow fibrosis and CD34-positive cell clusters in primary myelodysplastic syndromes. J. Clin. Oncol. 27, 754–762 (2009).
Lambertenghi-Deliliers, G. et al. Incidence and histological features of bone marrow involvement in malignant lymphomas. Ann. Hematol. 65, 61–65 (1992).
Schmid, C. & Isaacson, P. G. Bone marrow trephine biopsy in lymphoproliferative disease. J. Clin. Pathol. 45, 745–750 (1992).
Fend, F. & Kremer, M. Diagnosis and classification of malignant lymphoma and related entities in the bone marrow trephine biopsy. Pathobiology 74, 133–143 (2007).
Vega, F. et al. The stromal composition of malignant lymphoid aggregates in bone marrow: variations in architecture and phenotype in different B-cell tumours. Br. J. Haematol. 117, 569–576 (2002).
Florena, A. M. et al. Immunophenotypic profile and role of adhesion molecules in splenic marginal zone lymphoma with bone marrow involvement. Leuk. Lymphoma 47, 49–57 (2006).
Tripodo, C. et al. Gamma-delta T-cell lymphomas. Nat. Rev. Clin. Oncol. 6, 707–717 (2009).
Buchner, M. et al. Spleen tyrosine kinase inhibition prevents chemokine- and integrin-mediated stromal protective effects in chronic lymphocytic leukemia. Blood 115, 4497–4506 (2010).
Piccaluga, P. P. et al. Gene expression analysis provides a potential rationale for revising the histological grading of follicular lymphomas. Haematologica 93, 1033–1038 (2008).
Khokhar, F. A. et al. Angioimmunoblastic T-cell lymphoma in bone marrow: a morphologic and immunophenotypic study. Hum. Pathol. 41, 79–87 (2010).
Ilgenfritz, R. B. et al. Correlation between molecular and histopathological diagnoses of B cell lymphomas in bone marrow biopsy and aspirates. J. Clin. Pathol. 62, 357–360 (2009).
Skinnider, B. F., Connors, J. M. & Gascoyne, R. D. Bone marrow involvement in T-cell-rich B-cell lymphoma. Am. J. Clin. Pathol. 108, 570–578 (1997).
Gloghini, A., Colombatti, A., Bressan, G. & Carbone, A. Basement membrane components in lymphoid follicles: immunohistochemical demonstration and relationship to the follicular dendritic cell network. Hum. Pathol. 20, 1001–1007 (1989).
Li, Q. et al. Potential roles of follicular dendritic cell-associated osteopontin in lymphoid follicle pathology and repair and in B cell regulation in HIV-1 and SIV infection. J. Infect. Dis. 192, 1269–1276 (2005).
Yoon, S. O., Zhang, X., Berner, P., Blom, B. & Choi, Y. S. Notch ligands expressed by follicular dendritic cells protect germinal center B cells from apoptosis. J. Immunol. 183, 352–358 (2009).
Ayala, F., Dewar, R., Kieran, M. & Kalluri, R. Contribution of bone microenvironment to leukemogenesis and leukemia progression. Leukemia 23, 2233–2241 (2009).
Colmone, A. et al. Leukemic cells create bone marrow niches that disrupt the behavior of normal hematopoietic progenitor cells. Science 322, 1861–1865 (2008).
Negaard, H. F. et al. Increased bone marrow microvascular density in haematological malignancies is associated with differential regulation of angiogenic factors. Leukemia 23, 162–169 (2009).
Maffei, R. et al. Angiopoietin-2 plasma dosage predicts time to first treatment and overall survival in chronic lymphocytic leukemia. Blood 116, 584–592 (2010).
Piccaluga, P. P. et al. Gene expression analysis of angioimmunoblastic lymphoma indicates derivation from T follicular helper cells and vascular endothelial growth factor deregulation. Cancer Res. 67, 10703–10710 (2007).
Zucchetto, A. et al. CD38/CD31, the CCL3 and CCL4 chemokines, and CD49d/vascular cell adhesion molecule-1 are interchained by sequential events sustaining chronic lymphocytic leukemia cell survival. Cancer Res. 69, 4001–4009 (2009).
Tripodo, C. et al. Mast cells and Th17 cells contribute to the lymphoma-associated pro-inflammatory microenvironment of angioimmunoblastic T-cell lymphoma. Am. J. Pathol. 177, 792–802 (2010).
Treanor, B. et al. The membrane skeleton controls diffusion dynamics and signaling through the B cell receptor. Immunity 32, 187–199 (2010).
Franco, V., Tripodo, C., Rizzo, A., Stella, M. & Florena, A. M. Bone marrow biopsy in Hodgkin's lymphoma. Eur. J. Haematol. 73, 149–155 (2004).
Thiele, J., Zirbes, T. K., Kvasnicka, H. M. & Fischer, R. Focal lymphoid aggregates (nodules) in bone marrow biopsies: differentiation between benign hyperplasia and malignant lymphoma—a practical guideline. J. Clin. Pathol. 52, 294–300 (1999).
Rasmussen, T., Jensen, L. & Johnsen, H. E. The clonal hierachy in multiple myeloma. Acta Oncol. 39, 765–770 (2000).
Ghosh, N. & Matsui, W. Cancer stem cells in multiple myeloma. Cancer Lett. 277, 1–7 (2009).
Matsui, W. et al. Characterization of clonogenic multiple myeloma cells. Blood 103, 2332–2336 (2004).
Pilarski, L. M. et al. Leukemic B cells clonally identical to myeloma plasma cells are myelomagenic in NOD/SCID mice. Exp. Hematol. 30, 221–228 (2002).
Yaccoby, S. & Epstein, J. The proliferative potential of myeloma plasma cells manifest in the SCID-hu host. Blood 94, 3576–3582 (1999).
Hideshima, T., Nakamura, N., Chauhan, D. & Anderson, K. C. Biologic sequelae of interleukin-6 induced PI3-K/Akt signaling in multiple myeloma. Oncogene 20, 5991–6000 (2001).
Shain, K. H. et al. β1 integrin adhesion enhances IL-6-mediated STAT3 signaling in myeloma cells: implications for microenvironment influence on tumor survival and proliferation. Cancer Res. 69, 1009–1015 (2009).
Chauhan, D. et al. Multiple myeloma cell adhesion-induced interleukin-6 expression in bone marrow stromal cells involves activation of NF-kappa B. Blood 87, 1104–1112 (1996).
Sprynski, A. C. et al. The role of IGF-1 as a major growth factor for myeloma cell lines and the prognostic relevance of the expression of its receptor. Blood 113, 4614–4626 (2009).
Kveiborg, M., Flyvbjerg, A., Eriksen, E. F. & Kassem, M. Transforming growth factor-beta1 stimulates the production of insulin-like growth factor-I and insulin-like growth factor-binding protein-3 in human bone marrow stromal osteoblast progenitors. J. Endocrinol. 169, 549–561 (2001).
Edwards, C. M., Zhuang, J. & Mundy, G. R. The pathogenesis of the bone disease of multiple myeloma. Bone 42, 1007–1013 (2008).
Seidl, S., Kaufmann, H. & Drach, J. New insights into the pathophysiology of multiple myeloma. Lancet Oncol. 4, 557–564 (2003).
Terpos, E. & Dimopoulos, M. A. Myeloma bone disease: pathophysiology and management. Ann. Oncol. 16, 1223–1231 (2005).
Pinzone, J. J. et al. The role of Dickkopf-1 in bone development, homeostasis, and disease. Blood 113, 517–525 (2009).
Spisek, R. et al. Frequent and specific immunity to the embryonal stem cell-associated antigen SOX2 in patients with monoclonal gammopathy. J. Exp. Med. 204, 831–840 (2007).
Dhodapkar, K. M. et al. Dendritic cells mediate the induction of polyfunctional human IL17-producing cells (Th17–1 cells) enriched in the bone marrow of patients with myeloma. Blood 112, 2878–2885 (2008).
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).
Prabhala, R. H. et al. Elevated IL-17 produced by TH17 cells promotes myeloma cell growth and inhibits immune function in multiple myeloma. Blood 115, 5385–5392 (2010).
Kyle, R. A. & Rajkumar, S. V. Multiple myeloma. Blood 111, 2962–2972 (2008).
Gorgun, G. et al. Immunomodulatory effects of lenalidomide and pomalidomide on interaction of tumor and bone marrow accessory cells in multiple myeloma. Blood 116, 3227–3237 (2010).
Rajkumar, S. V., Richardson, P. G., Hideshima, T. & Anderson, K. C. Proteasome inhibition as a novel therapeutic target in human cancer. J. Clin. Oncol. 23, 630–639 (2005).
Thiele, J., Kvasnicka, H. M. & Schmitt-Graeff, A. Acute panmyelosis with myelofibrosis. Leuk. Lymphoma 45, 681–687 (2004).
Orazi, A. et al. Acute panmyelosis with myelofibrosis: an entity distinct from acute megakaryoblastic leukemia. Mod. Pathol. 18, 603–614 (2005).
Ryningen, A., Wergeland, L., Glenjen, N., Gjertsen, B. T. & Bruserud, O. In vitro crosstalk between fibroblasts and native human acute myelogenous leukemia (AML) blasts via local cytokine networks results in increased proliferation and decreased apoptosis of AML cells as well as increased levels of proangiogenic interleukin 8. Leuk. Res. 29, 185–196 (2005).
Veiga, J. P., Costa, L. F., Sallan, S. E., Nadler, L. M. & Cardoso, A. A. Leukemia-stimulated bone marrow endothelium promotes leukemia cell survival. Exp. Hematol. 34, 610–621 (2006).
Matsunaga, T. 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. 9, 1158–1165 (2003).
Li, W. W., Hutnik, M. & Gehr, G. Antiangiogenesis in haematological malignancies. Br. J. Haematol. 143, 622–631 (2008).
Burger, J. A. & Peled, A. CXCR4 antagonists: targeting the microenvironment in leukemia and other cancers. Leukemia 23, 43–52 (2009).
Thiele, J. et al. European consensus on grading bone marrow fibrosis and assessment of cellularity. Haematologica 90, 1128–1132 (2005).
Buesche, G. et al. Marrow fibrosis predicts early fatal marrow failure in patients with myelodysplastic syndromes. Leukemia 22, 313–322 (2008).
Malcovati, L. et al. Time-dependent prognostic scoring system for predicting survival and leukemic evolution in myelodysplastic syndromes. J. Clin. Oncol. 25, 3503–3510 (2007).
Greenberg, P. et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 89, 2079–2088 (1997).
Buesche, G. et al. Marrow fibrosis and its relevance during imatinib treatment of chronic myeloid leukemia. Leukemia 21, 2420–2427 (2007).
Tefferi, A., Skoda, R. & Vardiman, J.W. Myeloproliferative neoplasms: contemporary diagnosis using histology and genetics. Nat. Rev. Clin. Oncol. 6, 627–637 (2009).
Thiele, J., Kvasnicka, H. M. & Orazi, A. Bone marrow histopathology in myeloproliferative disorders—current diagnostic approach. Semin. Hematol. 42, 184–195 (2005).
Thiele, J. & Kvasnicka, H. M. Chronic myeloproliferative disorders with thrombocythemia: a comparative study of two classification systems (PVSG, WHO) on 839 patients. Ann. Hematol. 82, 148–152 (2003).
Bock, O. et al. Osteosclerosis in advanced chronic idiopathic myelofibrosis is associated with endothelial overexpression of osteoprotegerin. Br. J. Haematol. 130, 76–82 (2005).
Bock, O. et al. 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 (2008).
Steurer, M. et al. Increased angiogenesis in chronic idiopathic myelofibrosis: vascular endothelial growth factor as a prominent angiogenic factor. Hum. Pathol. 38, 1057–1064 (2007).
Chiu, A. et al. The stromal composition of mast cell aggregates in systemic mastocytosis. Mod. Pathol. 22, 857–865 (2009).
Tripodo, C. et al. CD146+ bone marrow osteoprogenitors increase in the advanced stages of primary myelofibrosis. Haematologica 94, 127–130 (2009).
Migliaccio, A. R. et al. Altered SDF-1/CXCR4 axis in patients with primary myelofibrosis and in the Gata1 low mouse model of the disease. Exp. Hematol. 36, 158–171 (2008).
Cho, S. Y. et al. The effect of CXCL12 processing on CD34+ cell migration in myeloproliferative neoplasms. Cancer Res. 70, 3402–3410 (2010).
Thiele, J. et al. Dynamics of bone marrow changes in patients with chronic idiopathic myelofibrosis following allogeneic stem cell transplantation. Histol. Histopathol. 20, 879–889 (2005).
Kluin-Nelemans, H. C. et al. Lenalidomide therapy in systemic mastocytosis. Leuk. Res. 33, e19–e22 (2009).
Lim, K. H., Pardanani, A., Butterfield, J. H., Li, C. Y. & Tefferi, A. Cytoreductive therapy in 108 adults with systemic mastocytosis: outcome analysis and response prediction during treatment with interferon-alpha, hydroxyurea, imatinib mesylate or 2-chlorodeoxyadenosine. Am. J. Hematol. 84, 790–794 (2009).
Hussong, J. W., Rodgers, G. M. & Shami, P. J. Evidence of increased angiogenesis in patients with acute myeloid leukemia. Blood 95, 309–313 (2000).
Padro, T. et al. Increased angiogenesis in the bone marrow of patients with acute myeloid leukemia. Blood 95, 2637–2644 (2000).
Lundberg, L. G. et al. Bone marrow in polycythemia vera, chronic myelocytic leukemia, and myelofibrosis has an increased vascularity. Am. J. Pathol. 157, 15–19 (2000).
Ponzoni, M. et al. Chronic idiopathic myelofibrosis: independent prognostic importance of bone marrow microvascular density evaluated by CD105 (endoglin) immunostaining. Mod. Pathol. 17, 1513–1520 (2004).
Kvasnicka, H. M. & Thiele, J. Bone marrow angiogenesis: methods of quantification and changes evolving in chronic myeloproliferative disorders. Histol. Histopathol. 19, 1245–1260 (2004).
Pruneri, G. et al. Angiogenesis in myelodysplastic syndromes. Br. J. Cancer 81, 1398–1401 (1999).
Kvasnicka, H. M. et al. Reversal of bone marrow angiogenesis in chronic myeloid leukemia following imatinib mesylate (STI571) therapy. Blood 103, 3549–3551 (2004).
Rambaldi, A., Barbui, T. & Barosi, G. From palliation to epigenetic therapy in myelofibrosis. Hematology Am. Soc. Hematol. Educ. Program 2008, 83–91 (2008).
Giles, F. J. et al. PTK787/ZK 222584, a small molecule tyrosine kinase receptor inhibitor of vascular endothelial growth factor (VEGF), has modest activity in myelofibrosis with myeloid metaplasia. Leuk. Res. 31, 891–897 (2007).
Mesa, R. A. et al. Lenalidomide and prednisone for myelofibrosis: Eastern Cooperative Oncology Group (ECOG) phase-2 trial E4903. Blood 116, 4436–4438 (2010).
Giles, F. J. et al. Phase II study of SU5416—a small-molecule, vascular endothelial growth factor tyrosine-kinase receptor inhibitor—in patients with refractory myeloproliferative diseases. Cancer 97, 1920–1928 (2003).
Rajkumar, S. V., Mesa, R. A. & Tefferi, A. A review of angiogenesis and anti-angiogenic therapy in hematologic malignancies. J. Hematother. Stem Cell Res. 11, 33–47 (2002).
Mueller, S. N. & Germain, R. N. Stromal cell contributions to the homeostasis and functionality of the immune system. Nat. Rev. Immunol. 9, 618–629 (2009).
Cathcart, K. et al. A multivalent bcr-abl fusion peptide vaccination trial in patients with chronic myeloid leukemia. Blood 103, 1037–1042 (2004).
Pinilla-Ibarz, J. et al. Vaccination of patients with chronic myelogenous leukemia with bcr-abl oncogene breakpoint fusion peptides generates specific immune responses. Blood 95, 1781–1787 (2000).
Yong, A. S. et al. High PR3 or ELA2 expression by CD34+ cells in advanced-phase chronic myeloid leukemia is associated with improved outcome following allogeneic stem cell transplantation and may improve PR1 peptide-driven graft-versus-leukemia effects. Blood 110, 770–775 (2007).
Wu, F. et al. Th1-biased humoral immune responses against Wilms tumor gene WT1 product in the patients with hematopoietic malignancies. Leukemia 19, 268–274 (2005).
Nauta, A. J. & Fibbe, W. E. Immunomodulatory properties of mesenchymal stromal cells. Blood 110, 3499–3506 (2007).
Di Nicola, M. et al. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood 99, 3838–3843 (2002).
Deng, W. et al. Effects of allogeneic bone marrow-derived mesenchymal stem cells on T and B lymphocytes from BXSB mice. DNA Cell Biol. 24, 458–463 (2005).
Meisel, R. et al. Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenase-mediated tryptophan degradation. Blood 103, 4619–4621 (2004).
Lepelletier, Y. et al. Galectin-1 and semaphorin-3A are two soluble factors conferring T-cell immunosuppression to bone marrow mesenchymal stem cell. Stem Cells Dev. 19, 1075–1079 (2010).
Gieseke, F. et al. Human multipotent mesenchymal stromal cells employ galectin-1 to inhibit immune effector cells. Blood 116, 3770–3779 (2010).
Nauta, A. J., Kruisselbrink, A. B., Lurvink, E., Willemze, R. & Fibbe, W. E. Mesenchymal stem cells inhibit generation and function of both CD34+-derived and monocyte-derived dendritic cells. J. Immunol. 177, 2080–2087 (2006).
Cheng, P., Zhou, J. & Gabrilovich, D. Regulation of dendritic cell differentiation and function by Notch and Wnt pathways. Immunol. Rev. 234, 105–119 (2010).
Prevosto, C., Zancolli, M., Canevali, P., Zocchi, M. R. & Poggi, A. Generation of CD4+ or CD8+ regulatory T cells upon mesenchymal stem cell-lymphocyte interaction. Haematologica 92, 881–888 (2007).
Colombo, M. P. & Piconese, S. Regulatory-T-cell inhibition versus depletion: the right choice in cancer immunotherapy. Nat. Rev. Cancer 7, 880–887 (2007).
Veldhoen, M., Hocking, R. J., Atkins, C. J., Locksley, R. M. & Stockinger, B. TGFβ in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24, 179–189 (2006).
Prabhala, R. H. et al. Dysfunctional T regulatory cells in multiple myeloma. Blood 107, 301–304 (2006).
Szczepanski, M. J. et al. Increased frequency and suppression by regulatory T cells in patients with acute myelogenous leukemia. Clin. Cancer Res. 15, 3325–3332 (2009).
Curti, A. et al. Modulation of tryptophan catabolism by human leukemic cells results in the conversion of CD25- into CD25+ T regulatory cells. Blood 109, 2871–2877 (2007).
Munn, D. H. et al. Prevention of allogeneic fetal rejection by tryptophan catabolism. Science 281, 1191–1193 (1998).
Kudo, Y. et al. Indoleamine 2,3-dioxygenase: distribution and function in the developing human placenta. J. Reprod. Immunol. 61, 87–98 (2004).
Gabrilovich, D. I. & Nagaraj, S. Myeloid-derived suppressor cells as regulators of the immune system. Nat. Rev. Immunol. 9, 162–174 (2009).
Ostrand-Rosenberg, S. & Sinha, P. Myeloid-derived suppressor cells: linking inflammation and cancer. J. Immunol. 182, 4499–4506 (2009).
Kong, Q. F. et al. Administration of bone marrow stromal cells ameliorates experimental autoimmune myasthenia gravis by altering the balance of Th1/Th2/Th17/Treg cell subsets through the secretion of TGF-β. J. Neuroimmunol. 207, 83–91 (2009).
Djouad, F. et al. Immunosuppressive effect of mesenchymal stem cells favors tumor growth in allogeneic animals. Blood 102, 3837–3844 (2003).
Le Blanc, K. et al. Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet 363, 1439–1441 (2004).
Zou, L. et al. Bone marrow is a reservoir for CD4+CD25+ regulatory T cells that traffic through CXCL12/CXCR4 signals. Cancer Res. 64, 8451–8455 (2004).
Miura, Y. et al. Mesenchymal stem cell-organized bone marrow elements: an alternative hematopoietic progenitor resource. Stem Cells 24, 2428–2436 (2006).
Gotoh, N. Control of stemness by fibroblast growth factor signaling in stem cells and cancer stem cells. Curr. Stem Cell Res. Ther. 4, 9–15 (2009).
Karlsson, S. Is TGF-β a stemness regulator? Blood 113, 1208 (2009).
Fibbe, W. E. & Willemze, R. The role of interleukin-1 in hematopoiesis. Acta Haematol. 86, 148–154 (1991).
Kopf, M. et al. Pleiotropic defects of IL-6-deficient mice including early hematopoiesis, T and B cell function, and acute phase responses. Ann. NY Acad. Sci. 762, 308–318 (1995).
Pearl-Yafe, M. et al. Tumor necrosis factor receptors support murine hematopoietic progenitor function in the early stages of engraftment. Stem Cells 28, 1270–1280 (2010).
Haylock, D. N. & Nilsson, S. K. Osteopontin: a bridge between bone and blood. Br. J. Haematol. 134, 467–474 (2006).
Emerson, S. G. Thrombopoietin, HSCs, and the osteoblast niche: holding on loosely, but not letting G0. Cell Stem Cell 1, 599–600 (2007).
The authors declare no competing financial interests.
About this article
Cite this article
Tripodo, C., Sangaletti, S., Piccaluga, P. et al. The bone marrow stroma in hematological neoplasms—a guilty bystander. Nat Rev Clin Oncol 8, 456–466 (2011). https://doi.org/10.1038/nrclinonc.2011.31
Blockade of VLA4 sensitizes leukemic and myeloma tumor cells to CD3 redirection in the bone marrow microenvironment
Blood Cancer Journal (2020)
Liposomal dexamethasone inhibits tumor growth in an advanced human-mouse hybrid model of multiple myeloma
Journal of Controlled Release (2019)
Annual Review of Cancer Biology (2019)
Perspective: Biophysical regulation of cancerous and normal blood cell lineages in hematopoietic malignancies
APL Bioengineering (2018)