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Stem Cells International
Volume 2017, Article ID 6720594, 13 pages
https://doi.org/10.1155/2017/6720594
Review Article

Mesenchymal Stem Cells in Myeloid Malignancies: A Focus on Immune Escaping and Therapeutic Implications

UO Onco-Hematology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Via F. Sforza 35, 20100 Milano, Italy

Correspondence should be addressed to Nicola Stefano Fracchiolla; ti.im.ocinilcilop@alloihccarf.n

Received 7 April 2017; Revised 6 June 2017; Accepted 20 July 2017; Published 21 August 2017

Academic Editor: Marcella Franquesa

Copyright © 2017 Nicola Stefano Fracchiolla et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. T. Walenda, S. Bork, P. Horn et al., “Co-culture with mesenchymal stromal cells increases proliferation and maintenance of haematopoietic progenitor cells,” Journal of Cellular and Molecular Medicine, vol. 14, no. 1-2, pp. 337–350, 2010. View at Publisher · View at Google Scholar · View at Scopus
  2. E. K. von der Heide, M. Neumann, S. Vosberg et al., “Molecular alterations in bone marrow mesenchymal stromal cells derived from acute myeloid leukemia patients,” Leukemia, vol. 31, no. 5, pp. 1069–1078, 2016. View at Publisher · View at Google Scholar · View at Scopus
  3. O. Blau, C. D. Baldus, W. K. Hofmann et al., “Mesenchymal stromal cells of myelodysplastic syndrome and acute myeloid leukemia patients have distinct genetic abnormalities compared with leukemic blasts,” Blood, vol. 118, no. 20, pp. 5583–5592, 2011. View at Publisher · View at Google Scholar · View at Scopus
  4. O. Blau, W. K. Hofmann, C. D. Baldus et al., “Chromosomal aberrations in bone marrow mesenchymal stroma cells from patients with myelodysplastic syndrome and acute myeloblastic leukemia,” Experimental Hematology, vol. 35, no. 2, pp. 221–229, 2007. View at Publisher · View at Google Scholar · View at Scopus
  5. M. C. Kastrinaki, C. Pontikoglou, M. Klaus, E. Stavroulaki, K. Pavlaki, and H. A. Papadaki, “Biologic characteristics of bone marrow mesenchymal stem cells in myelodysplastic syndromes,” Current Stem Cell Research & Therapy, vol. 6, no. 2, pp. 122–130, 2011. View at Publisher · View at Google Scholar · View at Scopus
  6. J. S. Heo, Y. Choi, H. S. Kim, and H. O. Kim, “Comparison of molecular profiles of human mesenchymal stem cells derived from bone marrow, umbilical cord blood, placenta and adipose tissue,” International Journal of Molecular Medicine, vol. 37, no. 1, pp. 115–125, 2016. View at Publisher · View at Google Scholar · View at Scopus
  7. M. F. Pittenger, A. M. Mackay, S. C. Beck et al., “Multilineage potential of adult human mesenchymal stem cells,” Science, vol. 284, no. 5411, pp. 143–147, 1999. View at Publisher · View at Google Scholar · View at Scopus
  8. S. Méndez-Ferrer, T. V. Michurina, F. Ferraro et al., “Mesenchymal and haematopoietic stem cells form a unique bone marrow niche,” Nature, vol. 466, no. 7308, pp. 829–834, 2010. View at Publisher · View at Google Scholar · View at Scopus
  9. B. Sacchetti, A. Funari, S. Michienzi et al., “Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment,” Cell, vol. 131, no. 2, pp. 324–336, 2007. View at Publisher · View at Google Scholar · View at Scopus
  10. M. Dominici, K. Le Blanc, I. Mueller et al., “Minimal criteria for defining multipotent mesenchymal stromal cells. The international society for cellular therapy position statement,” Cytotherapy, vol. 8, no. 4, pp. 315–317, 2006. View at Publisher · View at Google Scholar · View at Scopus
  11. J. E. Dennis and P. Charbord, “Origin and differentiation of human and murine stroma,” Stem Cells, vol. 20, no. 3, pp. 205–214, 2002. View at Publisher · View at Google Scholar
  12. A. B. Salter, S. K. Meadows, G. G. Muramoto et al., “Endothelial progenitor cell infusion induces hematopoietic stem cell reconstitution in vivo,” Blood, vol. 113, no. 9, pp. 2104–2107, 2009. View at Publisher · View at Google Scholar · View at Scopus
  13. L. Ding, T. L. Saunders, G. Enikolopov, and S. J. Morrison, “Endothelial and perivascular cells maintain haematopoietic stem cells,” Nature, vol. 481, no. 7382, pp. 457–462, 2012. View at Publisher · View at Google Scholar · View at Scopus
  14. I. G. Winkler, V. Barbier, B. Nowlan et al., “Vascular niche E-selectin regulates hematopoietic stem cell dormancy, self renewal and chemoresistance,” Nature Medicine, vol. 18, no. 11, pp. 1651–1657, 2012. View at Publisher · View at Google Scholar · View at Scopus
  15. J. P. Lévesque, F. M. Helwani, and I. G. Winkler, “The endosteal ‘osteoblastic’ niche and its role in hematopoietic stem cell homing and mobilization,” Leukemia, vol. 24, no. 12, pp. 1979–1992, 2010. View at Publisher · View at Google Scholar · View at Scopus
  16. M. Das, S. Chatterjee, P. Basak et al., “The bone marrow stem stromal imbalance—a key feature of disease progression in case of myelodysplastic mouse model,” Journal of Stem Cells, vol. 5, no. 2, pp. 49–64, 2010. View at Google Scholar
  17. S. Mishima, A. Nagai, S. Abdullah et al., “Effective ex vivo expansion of hematopoietic stem cells using osteoblast-differentiated mesenchymal stem cells is CXCL12 dependent,” European Journal of Haematology, vol. 84, no. 6, pp. 538–546, 2010. View at Publisher · View at Google Scholar · View at Scopus
  18. T. Sugiyama, H. Kohara, M. Noda, and T. Nagasawa, “Maintenance of the hematopoietic stem cell pool by CXCL12-CXCR4 chemokine signaling in bone marrow stromal cell niches,” Immunity, vol. 25, no. 6, pp. 977–988, 2006. View at Publisher · View at Google Scholar · View at Scopus
  19. A. Greenbaum, Y. M. Hsu, R. B. Day et al., “CXCL12 in early mesenchymal progenitors is required for haematopoietic stem-cell maintenance,” Nature, vol. 495, no. 7440, pp. 227–230, 2013. View at Publisher · View at Google Scholar · View at Scopus
  20. A. Uccelli, V. Pistoia, and L. Moretta, “Mesenchymal stem cells: a new strategy for immunosuppression?” Trends in Immunology, vol. 28, no. 5, pp. 219–226, 2007. View at Publisher · View at Google Scholar · View at Scopus
  21. S. Zhao, R. Wehner, M. Bornhauser, R. Wassmuth, M. Bachmann, and M. Schmitz, “Immunomodulatory properties of mesenchymal stromal cells and their therapeutic consequences for immune-mediated disorders,” Stem Cells and Development, vol. 19, no. 5, pp. 607–614, 2010. View at Publisher · View at Google Scholar · View at Scopus
  22. P. Mattar and K. Bieback, “Comparing the immunomodulatory properties of bone marrow, adipose tissue, and birth-associated tissue mesenchymal stromal cells,” Frontiers in Immunology, vol. 6, p. 560, 2015. View at Publisher · View at Google Scholar · View at Scopus
  23. D. Wolf and A. M. Wolf, “Mesenchymal stem cells as cellular immunosuppressants,” Lancet, vol. 371, no. 9624, pp. 1553-1554, 2008. View at Publisher · View at Google Scholar · View at Scopus
  24. M. Najar, G. Raicevic, E. Crompot et al., “The immunomodulatory potential of mesenchymal stromal cells: a story of a regulatory network,” Journal of Immunotherapy, vol. 39, no. 2, pp. 45–59, 2016. View at Publisher · View at Google Scholar · View at Scopus
  25. M. Najar, G. Raicevic, H. Fayyad-Kazan, D. Bron, M. Toungouz, and L. Lagneaux, “Mesenchymal stromal cells and immunomodulation: a gathering of regulatory immune cells,” Cytotherapy, vol. 18, no. 2, pp. 160–171, 2016. View at Publisher · View at Google Scholar · View at Scopus
  26. A. Augello, R. Tasso, S. M. Negrini et al., “Bone marrow mesenchymal progenitor cells inhibit lymphocyte proliferation by activation of the programmed death 1 pathway,” European Journal of Immunology, vol. 35, no. 5, pp. 1482–1490, 2005. View at Publisher · View at Google Scholar · View at Scopus
  27. Y. Z. Hu, Q. Xue, Y. J. Chen et al., “Different roles of PD-L1 and FasL in immunomodulation mediated by human placenta-derived mesenchymal stem cells,” Human Immunology, vol. 74, no. 3, pp. 267–276, 2013. View at Publisher · View at Google Scholar · View at Scopus
  28. S. Ghannam, J. Pene, G. Moquet-Torcy, C. Jorgensen, and H. Yssel, “Mesenchymal stem cells inhibit human Th17 cell differentiation and function and induce a T regulatory cell phenotype,” Journal of Immunology, vol. 185, no. 1, pp. 302–312, 2010. View at Publisher · View at Google Scholar · View at Scopus
  29. P. Luz-Crawford, D. Noel, X. Fernandez et al., “Mesenchymal stem cells repress Th17 molecular program through the PD-1 pathway,” PLoS One, vol. 7, no. 9, article e45272, 2012. View at Publisher · View at Google Scholar · View at Scopus
  30. C. Iancu-Rubin, G. Mosoyan, J. Wang, T. Kraus, V. Sung, and R. Hoffman, “Stromal cell-mediated inhibition of erythropoiesis can be attenuated by Sotatercept (ACE-011), an activin receptor type II ligand trap,” Experimental Hematology, vol. 41, no. 2, pp. 155–166, 2013. View at Publisher · View at Google Scholar · View at Scopus
  31. D. B. Chou, B. Sworder, N. Bouladoux et al., “Stromal-derived IL-6 alters the balance of myeloerythroid progenitors during Toxoplasma gondii infection,” Journal of Leukocyte Biology, vol. 92, no. 1, pp. 123–131, 2012. View at Publisher · View at Google Scholar · View at Scopus
  32. R. Del Toro and S. Mendez-Ferrer, “Autonomic regulation of hematopoiesis and cancer,” Haematologica, vol. 98, no. 11, pp. 1663–1666, 2013. View at Publisher · View at Google Scholar · View at Scopus
  33. L. Arranz, A. Sánchez-Aguilera, D. Martín-Pérez et al., “Neuropathy of haematopoietic stem cell niche is essential for myeloproliferative neoplasms,” Nature, vol. 512, no. 7512, pp. 78–81, 2014. View at Publisher · View at Google Scholar · View at Scopus
  34. L. Pleyer, P. Valent, and R. Greil, “Mesenchymal stem and progenitor cells in normal and dysplastic hematopoiesis-masters of survival and clonality?” International Journal of Molecular Sciences, vol. 17, no. 7, 2016. View at Publisher · View at Google Scholar · View at Scopus
  35. O. Lopez-Villar, J. L. Garcia, F. M. Sanchez-Guijo et al., “Both expanded and uncultured mesenchymal stem cells from MDS patients are genomically abnormal, showing a specific genetic profile for the 5q-syndrome,” Leukemia, vol. 23, no. 4, pp. 664–672, 2009. View at Publisher · View at Google Scholar · View at Scopus
  36. H. Gul-Uludag, J. Valencia-Serna, C. Kucharski et al., “Polymeric nanoparticle-mediated silencing of CD44 receptor in CD34 acute myeloid leukemia cells,” Leukemia Research, vol. 38, no. 11, pp. 1299–1308, 2014. View at Publisher · View at Google Scholar · View at Scopus
  37. L. Teofili, M. Martini, E. R. Nuzzolo et al., “Endothelial progenitor cell dysfunction in myelodysplastic syndromes: possible contribution of a defective vascular niche to myelodysplasia,” Neoplasia, vol. 17, no. 5, pp. 401–409, 2015. View at Publisher · View at Google Scholar · View at Scopus
  38. S. Abe-Suzuki, M. Kurata, S. Abe et al., “CXCL12+ stromal cells as bone marrow niche for CD34+ hematopoietic cells and their association with disease progression in myelodysplastic syndromes,” Laboratory Investigation, vol. 94, no. 11, pp. 1212–1223, 2014. View at Publisher · View at Google Scholar · View at Scopus
  39. L. Zhou, A. N. Nguyen, D. Sohal et al., “Inhibition of the TGF-βreceptor I kinase promotes hematopoiesis in MDS,” Blood, vol. 112, no. 8, pp. 3434–3443, 2008. View at Publisher · View at Google Scholar · View at Scopus
  40. A. Wierzbowska, T. Robak, A. Krawczynska et al., “Circulating endothelial cells in patients with acute myeloid leukemia,” European Journal of Haematology, vol. 75, no. 6, pp. 492–497, 2005. View at Publisher · View at Google Scholar · View at Scopus
  41. B. Pezeshkian, C. Donnelly, K. Tamburo, T. Geddes, and G. J. Madlambayan, “Leukemia mediated endothelial cell activation modulates leukemia cell susceptibility to chemotherapy through a positive feedback loop mechanism,” PLoS One, vol. 8, no. 4, article e60823, 2013. View at Publisher · View at Google Scholar · View at Scopus
  42. J. C. Huang, S. K. Basu, X. Zhao et al., “Mesenchymal stromal cells derived from acute myeloid leukemia bone marrow exhibit aberrant cytogenetics and cytokine elaboration,” Blood Cancer Journal, vol. 5, no. 4, article e302, 2015. View at Publisher · View at Google Scholar · View at Scopus
  43. A. K. Brenner, I. Nepstad, and Ø. Bruserud, “Mesenchymal stem cells support survival and proliferation of primary human acute myeloid leukemia cells through heterogeneous molecular mechanisms,” Frontiers in Immunology, vol. 8, p. 106, 2017. View at Publisher · View at Google Scholar
  44. M. Rodrigues Lopes, J. K. N. Pereira, C. P. de Melo et al., “De novo AML exhibits greater microenvironment dysregulation compared to AML with myelodysplasia-related changes,” Scientific Reports, vol. 7, article 40707, 2017. View at Publisher · View at Google Scholar
  45. M. Hanoun, D. Zhang, T. Mizoguchi et al., “Acute myelogenous leukemia-induced sympathetic neuropathy promotes malignancy in an altered hematopoietic stem cell niche,” Cell Stem Cell, vol. 15, no. 3, pp. 365–375, 2014. View at Publisher · View at Google Scholar · View at Scopus
  46. A. Kode, J. S. Manavalan, I. Mosialou et al., “Leukaemogenesis induced by an activating beta-catenin mutation in osteoblasts,” Nature, vol. 506, no. 7487, pp. 240–244, 2014. View at Publisher · View at Google Scholar · View at Scopus
  47. M. H. Raaijmakers, S. Mukherjee, S. Guo et al., “Bone progenitor dysfunction induces myelodysplasia and secondary leukaemia,” Nature, vol. 464, no. 7290, pp. 852–857, 2010. View at Publisher · View at Google Scholar · View at Scopus
  48. R. Diaz de la Guardia, B. Lopez-Millan, J. R. Lavoie et al., “Detailed characterization of mesenchymal stem/stromal cells from a large cohort of AML patients demonstrates a definitive link to treatment outcomes,” Stem Cell Reports, vol. 8, no. 6, pp. 1573–1586, 2017. View at Publisher · View at Google Scholar
  49. S. Chen, N. A. Zambetti, E. M. Bindels et al., “Massive parallel RNA sequencing of highly purified mesenchymal elements in low-risk MDS reveals tissue-context-dependent activation of inflammatory programs,” Leukemia, vol. 30, no. 9, pp. 1938–1942, 2016. View at Publisher · View at Google Scholar · View at Scopus
  50. Y. Mosesson, G. B. Mills, and Y. Yarden, “Derailed endocytosis: an emerging feature of cancer,” Nature Reviews Cancer, vol. 8, no. 11, pp. 835–850, 2008. View at Publisher · View at Google Scholar · View at Scopus
  51. S. Sigismund, S. Confalonieri, A. Ciliberto, S. Polo, G. Scita, and P. P. Di Fiore, “Endocytosis and signaling: cell logistics shape the eukaryotic cell plan,” Physiological Reviews, vol. 92, no. 1, pp. 273–366, 2012. View at Publisher · View at Google Scholar · View at Scopus
  52. A. Sorkin and M. von Zastrow, “Endocytosis and signalling: intertwining molecular networks,” Nature Reviews Molecular Cell Biology, vol. 10, no. 9, pp. 609–622, 2009. View at Publisher · View at Google Scholar · View at Scopus
  53. V. Carito, G. Bonuccelli, U. E. Martinez-Outschoorn et al., “Metabolic remodeling of the tumor microenvironment: migration stimulating factor (MSF) reprograms myofibroblasts toward lactate production, fueling anabolic tumor growth,” Cell Cycle, vol. 11, no. 18, pp. 3403–3414, 2012. View at Publisher · View at Google Scholar · View at Scopus
  54. R. Moschoi, V. Imbert, M. Nebout et al., “Protective mitochondrial transfer from bone marrow stromal cells to acute myeloid leukemic cells during chemotherapy,” Blood, vol. 128, no. 2, pp. 253–264, 2016. View at Publisher · View at Google Scholar
  55. L. Guo, N. Cui, H. Wang et al., “Autophagy level of bone marrow mononuclear cells in patients with myelodysplastic syndromes,” Zhonghua Xue Ye Xue Za Zhi, vol. 36, no. 12, pp. 1016–1019, 2015. View at Publisher · View at Google Scholar · View at Scopus
  56. E. J. Houwerzijl, H. W. Pol, N. R. Blom, J. J. van der Want, J. T. de Wolf, and E. Vellenga, “Erythroid precursors from patients with low-risk myelodysplasia demonstrate ultrastructural features of enhanced autophagy of mitochondria,” Leukemia, vol. 23, no. 5, pp. 886–891, 2009. View at Publisher · View at Google Scholar · View at Scopus
  57. S. Y. Wan, R. Zhang, Y. Y. Wang et al., “Expression of autophagy related gene Beclin1 in myelodysplastic syndrome patients and its significance,” Zhongguo Shi Yan Xue Ye Xue Za Zhi, vol. 21, no. 4, pp. 936–939, 2013. View at Google Scholar
  58. H. Karlic, H. Herrmann, F. Varga et al., “The role of epigenetics in the regulation of apoptosis in myelodysplastic syndromes and acute myeloid leukemia,” Critical Reviews in Oncology/Hematology, vol. 90, no. 1, pp. 1–16, 2014. View at Publisher · View at Google Scholar · View at Scopus
  59. C. Y. Dong, X. Y. Liu, N. Wang et al., “Twist-1, a novel regulator of hematopoietic stem cell self-renewal and myeloid lineage development,” Stem Cells, vol. 32, no. 12, pp. 3173–3182, 2014. View at Publisher · View at Google Scholar · View at Scopus
  60. N. Merindol, A. Riquet, V. Szablewski, J. F. Eliaou, A. Puisieux, and N. Bonnefoy, “The emerging role of Twist proteins in hematopoietic cells and hematological malignancies,” Blood Cancer Journal, vol. 4, article e206, 2014. View at Publisher · View at Google Scholar · View at Scopus
  61. A. J. Mhyre, A. M. Marcondes, E. Y. Spaulding, and H. J. Deeg, “Stroma-dependent apoptosis in clonal hematopoietic precursors correlates with expression of PYCARD,” Blood, vol. 113, no. 3, pp. 649–658, 2009. View at Publisher · View at Google Scholar · View at Scopus
  62. X. Zhang, W. Ma, J. Cui et al., “Regulation of p21 by TWIST2 contributes to its tumor-suppressor function in human acute myeloid leukemia,” Oncogene, vol. 34, no. 23, pp. 3000–3010, 2015. View at Publisher · View at Google Scholar · View at Scopus
  63. G. Varga, J. Kiss, J. Varkonyi et al., “Inappropriate notch activity and limited mesenchymal stem cell plasticity in the bone marrow of patients with myelodysplastic syndromes,” Pathology Oncology Research, vol. 13, no. 4, pp. 311–319, 2007. View at Publisher · View at Google Scholar
  64. S. Geyh, M. Rodríguez-Paredes, P. Jäger et al., “Functional inhibition of mesenchymal stromal cells in acute myeloid leukemia,” Leukemia, vol. 30, no. 3, pp. 683–691, 2015. View at Publisher · View at Google Scholar · View at Scopus
  65. A. Glenthøj, A. D. Ørskov, J. W. Hansen, S. R. Hadrup, C. O'Connell, and K. Grønbæk, “Immune mechanisms in myelodysplastic syndrome,” International Journal of Molecular Sciences, vol. 17, no. 6, 2016. View at Publisher · View at Google Scholar · View at Scopus
  66. W. Barcellini, B. Fattizzo, A. Zaninoni et al., “Clinical evolution of autoimmune cytopenias to idiopathic cytopenias/dysplasias of uncertain significance (ICUS/IDUS) and bone marrow failure syndromes,” American Journal of Hematology, vol. 92, no. 3, pp. E26–E29, 2017. View at Publisher · View at Google Scholar
  67. M. Kitagawa, I. Saito, T. Kuwata et al., “Overexpression of tumor necrosis factor (TNF)-α and interferon (IFN)-gamma by bone marrow cells from patients with myelodysplastic syndromes,” Leukemia, vol. 11, no. 12, pp. 2049–2054, 1997. View at Google Scholar
  68. G. Stifter, S. Heiss, G. Gastl, A. Tzankov, and R. Stauder, “Over-expression of tumor necrosis factor-α in bone marrow biopsies from patients with myelodysplastic syndromes: relationship to anemia and prognosis,” European Journal of Haematology, vol. 75, no. 6, pp. 485–491, 2005. View at Publisher · View at Google Scholar · View at Scopus
  69. S. Giannouli, T. Kanellopoulou, and M. Voulgarelis, “Myelodysplasia and autoimmunity,” Current Opinion in Rheumatology, vol. 24, no. 1, pp. 97–102, 2012. View at Publisher · View at Google Scholar · View at Scopus
  70. D. T. Starczynowski, F. Kuchenbauer, B. Argiropoulos et al., “Identification of miR-145 and miR-146a as mediators of the 5q-syndrome phenotype,” Nature Medicine, vol. 16, no. 1, pp. 49–58, 2010. View at Publisher · View at Google Scholar · View at Scopus
  71. R. Austin, M. J. Smyth, and S. W. Lane, “Harnessing the immune system in acute myeloid leukaemia,” Critical Reviews in Oncology/Hematology, vol. 103, pp. 62–77, 2016. View at Publisher · View at Google Scholar · View at Scopus
  72. M. Goswami, G. Prince, A. Biancotto et al., “Impaired B cell immunity in acute myeloid leukemia patients after chemotherapy,” Journal of Translational Medicine, vol. 15, no. 1, p. 155, 2017. View at Publisher · View at Google Scholar
  73. L. Sadeghi, M. H. Karimi, E. Kamali-Sarvestani, N. Azarpira, and M. Shariati, “The Immunomodulatory effect of bone-marrow mesenchymal stem cells on expression of TLR3 and TLR9 in mice dendritic cells,” International Journal of Organ Transplantation Medicine, vol. 8, no. 1, pp. 35–42, 2017. View at Google Scholar
  74. V. Pistoia and L. Raffaghello, “Mesenchymal stromal cells and autoimmunity,” International Immunology, vol. 29, no. 2, pp. 49–58, 2017. View at Publisher · View at Google Scholar
  75. R. Baharlou, A. Ahmadi-Vasmehjani, F. Faraji et al., “Human adipose tissue-derived mesenchymal stem cells in rheumatoid arthritis: regulatory effects on peripheral blood mononuclear cells activation,” International Immunopharmacology, vol. 47, pp. 59–69, 2017. View at Publisher · View at Google Scholar
  76. Z. Sun, S. Wang, and R. C. Zhao, “The roles of mesenchymal stem cells in tumor inflammatory microenvironment,” Journal of Hematology & Oncology, vol. 7, p. 14, 2014. View at Publisher · View at Google Scholar · View at Scopus
  77. R. S. Waterman, S. L. Tomchuck, S. L. Henkle, and A. M. Betancourt, “A new mesenchymal stem cell (MSC) paradigm: polarization into a pro-inflammatory MSC1 or an immunosuppressive MSC2 phenotype,” PLoS One, vol. 5, no. 4, article e10088, 2010. View at Publisher · View at Google Scholar · View at Scopus
  78. R. Rodriguez, M. Rosu-Myles, M. Aráuzo-Bravo et al., “Human bone marrow stromal cells lose immunosuppressive and anti-inflammatory properties upon oncogenic transformation,” Stem Cell Reports, vol. 3, no. 4, pp. 606–619, 2014. View at Publisher · View at Google Scholar · View at Scopus
  79. A. Agliano, A. Calvo, and C. Box, “The challenge of targeting cancer stem cells to halt metastasis,” Seminars in Cancer Biology, vol. 44, pp. 25–42, 2017. View at Publisher · View at Google Scholar
  80. J. Paggetti, F. Haderk, M. Seiffert et al., “Exosomes released by chronic lymphocytic leukemia cells induce the transition of stromal cells into cancer-associated fibroblasts,” Blood, vol. 126, no. 9, pp. 1106–1117, 2015. View at Publisher · View at Google Scholar · View at Scopus
  81. A. Poggi, A. Musso, I. Dapino, and M. R. Zocchi, “Mechanisms of tumor escape from immune system: role of mesenchymal stromal cells,” Immunology Letters, vol. 159, no. 1-2, pp. 55–72, 2014. View at Publisher · View at Google Scholar · View at Scopus
  82. K. Suzuki, R. Sun, M. Origuchi et al., “Mesenchymal stromal cells promote tumor growth through the enhancement of neovascularization,” Molecular Medicine, vol. 17, no. 7-8, pp. 579–587, 2011. View at Publisher · View at Google Scholar · View at Scopus
  83. R. Ramasamy, E. W. Lam, I. Soeiro, V. Tisato, D. Bonnet, and F. Dazzi, “Mesenchymal stem cells inhibit proliferation and apoptosis of tumor cells: impact on in vivo tumor growth,” Leukemia, vol. 21, no. 2, pp. 304–310, 2007. View at Publisher · View at Google Scholar · View at Scopus
  84. P. D. Johann and I. Muller, “Multipotent mesenchymal stromal cells: possible culprits in solid tumors?” Stem Cells International, vol. 2015, Article ID 914632, 11 pages, 2015. View at Publisher · View at Google Scholar · View at Scopus
  85. Z. G. Zhao, W. M. Li, Z. C. Chen, Y. You, and P. Zou, “Immunosuppressive properties of mesenchymal stem cells derived from bone marrow of patients with chronic myeloid leukemia,” Immunological Investigations, vol. 37, no. 7, pp. 726–739, 2008. View at Publisher · View at Google Scholar · View at Scopus
  86. W. Ling, J. Zhang, Z. Yuan et al., “Mesenchymal stem cells use IDO to regulate immunity in tumor microenvironment,” Cancer Research, vol. 74, no. 5, pp. 1576–1587, 2014. View at Publisher · View at Google Scholar · View at Scopus
  87. T. Li, Y. Yang, X. Hua et al., “Hepatocellular carcinoma-associated fibroblasts trigger NK cell dysfunction via PGE2 and IDO,” Cancer Letters, vol. 318, no. 2, pp. 154–161, 2012. View at Publisher · View at Google Scholar · View at Scopus
  88. C. Uyttenhove, L. Pilotte, I. Theate et al., “Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase,” Nature Medicine, vol. 9, no. 10, pp. 1269–1274, 2003. View at Publisher · View at Google Scholar · View at Scopus
  89. Y. W. Moon, J. Hajjar, P. Hwu, and A. Naing, “Targeting the indoleamine 2,3-dioxygenase pathway in cancer,” Journal for Immunotherapy of Cancer, vol. 3, p. 51, 2015. View at Publisher · View at Google Scholar · View at Scopus
  90. I. Mansour, R. A. Zayed, F. Said, and L. A. Latif, “Indoleamine 2,3-dioxygenase and regulatory T cells in acute myeloid leukemia,” Hematology, vol. 21, no. 8, pp. 447–453, 2016. View at Publisher · View at Google Scholar · View at Scopus
  91. Z. Zhi-Gang, L. Wei-Ming, C. Zhi-Chao, Y. Yong, and Z. Ping, “Immunosuppressive properties of mesenchymal stem cells derived from bone marrow of patient with hematological malignant diseases,” Leukemia & Lymphoma, vol. 49, no. 11, pp. 2187–2195, 2008. View at Publisher · View at Google Scholar · View at Scopus
  92. Z. Wang, X. Tang, W. Xu 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, vol. 8, no. 3, article e57470, 2013. View at Publisher · View at Google Scholar · View at Scopus
  93. Z. G. Zhao, W. Xu, H. P. Yu et al., “Functional characteristics of mesenchymal stem cells derived from bone marrow of patients with myelodysplastic syndromes,” Cancer Letters, vol. 317, no. 2, pp. 136–143, 2012. View at Publisher · View at Google Scholar · View at Scopus
  94. S. Corm, C. Berthon, M. Imbenotte et al., “Indoleamine 2,3-dioxygenase activity of acute myeloid leukemia cells can be measured from patients’sera by HPLC and is inducible by IFN-gamma,” Leukemia Research, vol. 33, no. 3, pp. 490–494, 2009. View at Publisher · View at Google Scholar · View at Scopus
  95. M. E. Chamuleau, A. A. van de Loosdrecht, C. J. Hess et al., “High INDO (indoleamine 2,3-dioxygenase) mRNA level in blasts of acute myeloid leukemic patients predicts poor clinical outcome,” Haematologica, vol. 93, no. 12, pp. 1894–1898, 2008. View at Publisher · View at Google Scholar · View at Scopus
  96. C. Berthon, M. Fontenay, S. Corm et al., “Metabolites of tryptophan catabolism are elevated in sera of patients with myelodysplastic syndromes and inhibit hematopoietic progenitor amplification,” Leukemia Research, vol. 37, no. 5, pp. 573–579, 2013. View at Publisher · View at Google Scholar · View at Scopus
  97. T. Tian, S. Yu, L. Liu et al., “The profile of T helper subsets in bone marrow microenvironment is distinct for different stages of acute myeloid leukemia patients and chemotherapy partly ameliorates these variations,” PLoS One, vol. 10, article e013176, 2015. View at Publisher · View at Google Scholar · View at Scopus
  98. F. G. Calkoen, C. Vervat, E. Eising et al., “Gene-expression and in vitro function of mesenchymal stromal cells are affected in juvenile myelomonocytic leukemia,” Haematologica, vol. 100, no. 11, pp. 1434–1441, 2015. View at Publisher · View at Google Scholar · View at Scopus
  99. J. Vasold, M. Wagner, H. Drolle et al., “The bone marrow microenvironment is a critical player in the NK cell response against acute myeloid leukaemia in vitro,” Leukemia Research, vol. 39, no. 2, pp. 257–262, 2015. View at Publisher · View at Google Scholar · View at Scopus
  100. J. Cannova, S. J. P. Breslin, and J. Zhang, “Toll-like receptor signaling in hematopoietic homeostasis and the pathogenesis of hematologic diseases,” Frontiers in Medicine, vol. 9, no. 3, pp. 288–303, 2015. View at Publisher · View at Google Scholar · View at Scopus
  101. Y. Wei, S. Dimicoli, C. Bueso-Ramos et al., “Toll-like receptor alterations in myelodysplastic syndrome,” Leukemia, vol. 27, no. 9, pp. 1832–1840, 2013. View at Publisher · View at Google Scholar · View at Scopus
  102. Q. Zeng, J. Shu, Q. Hu et al., “Apoptosis in human myelodysplastic syndrome CD34+ cells is modulated by the upregulation of TLRs and histone H4 acetylation via a beta-arrestin 1 dependent mechanism,” Experimental Cell Research, vol. 340, no. 1, pp. 22–31, 2016. View at Publisher · View at Google Scholar · View at Scopus
  103. S. Dimicoli, Y. Wei, C. Bueso-Ramos et al., “Overexpression of the toll-like receptor (TLR) signaling adaptor MYD88, but lack of genetic mutation, in myelodysplastic syndromes,” PLoS One, vol. 8, no. 8, article e71120, 2013. View at Publisher · View at Google Scholar · View at Scopus
  104. S. L. Tomchuck, K. J. Zwezdaryk, S. B. Coffelt, R. S. Waterman, E. S. Danka, and A. B. Scandurro, “Toll-like receptors on human mesenchymal stem cells drive their migration and immunomodulating responses,” Stem Cells, vol. 26, no. 1, pp. 99–107, 2008. View at Publisher · View at Google Scholar · View at Scopus
  105. J. J. Ignatz-Hoover, H. Wang, S. A. Moreton et al., “The role of TLR8 signaling in acute myeloid leukemia differentiation,” Leukemia, vol. 29, no. 4, pp. 918–926, 2015. View at Publisher · View at Google Scholar · View at Scopus
  106. A. Entrena, A. Varas, M. Vázquez et al., “Mesenchymal stem cells derived from low risk acute lymphoblastic leukemia patients promote NK cell antitumor activity,” Cancer Letters, vol. 363, no. 2, pp. 156–165, 2015. View at Publisher · View at Google Scholar · View at Scopus
  107. C. Giallongo, A. Romano, N. L. Parrinello et al., “Mesenchymal stem cells (MSC) regulate activation of granulocyte-like myeloid derived suppressor cells (G-MDSC) in chronic myeloid leukemia patients,” PLoS One, vol. 11, article e0158392, 2016. View at Publisher · View at Google Scholar · View at Scopus
  108. A. Sehgal, T. L. Whiteside, and M. Boyiadzis, “PD-1 checkpoint blockade in acute myeloid leukemia,” Expert Opinion on Biological Therapy, vol. 15, no. 8, pp. 1191–1203, 2015. View at Publisher · View at Google Scholar · View at Scopus
  109. J. Li, J. Chen, X. Li, and Y. Qian, “Vaccination efficacy with marrow mesenchymal stem cell against cancer was enhanced under simulated microgravity,” Biochemical and Biophysical Research Communications, vol. 485, no. 3, pp. 606–613, 2017. View at Publisher · View at Google Scholar
  110. R. Aliperta, M. Cartellieri, A. Feldmann et al., “Bispecific antibody releasing-mesenchymal stromal cell machinery for retargeting T cells towards acute myeloid leukemia blasts,” Blood Cancer Journal, vol. 5, article e348, 2015. View at Publisher · View at Google Scholar · View at Scopus
  111. A. Castleton, A. Dey, B. Beaton et al., “Human mesenchymal stromal cells deliver systemic oncolytic measles virus to treat adcute lymphoblastic leukemia in the presence of humoral immunity,” Blood, vol. 123, no. 9, pp. 1327–1335, 2014. View at Publisher · View at Google Scholar · View at Scopus
  112. S. Ninomiya, N. Narala, L. Huye et al., “Tumor indoleamine 2,3-dioxygenase (IDO) inhibits CD19-CAR T cells and is downregulated by lymphodepleting drugs,” Blood, vol. 125, no. 25, pp. 3905–3916, 2015. View at Publisher · View at Google Scholar · View at Scopus
  113. C. Berthon, V. Driss, J. Liu et al., “In acute myeloid leukemia, B7-H1 (PD-L1) protection of blasts from cytotoxic T cells is induced by TLR ligands and interferon-gammaand can be reversed using MEK inhibitors,” Cancer Immunology, Immunotherapy, vol. 59, no. 12, pp. 1839–1849, 2010. View at Publisher · View at Google Scholar · View at Scopus
  114. B. Beck, D. Dorfel, F. S. Lichtenegger et al., “Effects of TLR agonists on maturation and function of 3-day dendritic cells from AML patients in complete remission,” Journal of Translational Medicine, vol. 9, p. 151, 2011. View at Publisher · View at Google Scholar · View at Scopus
  115. E. L. Smits, N. Cools, E. Lion et al., “The toll-like receptor 7/8 agonist resiquimod greatly increases the immunostimulatory capacity of human acute myeloid leukemia cells,” Cancer Immunology, Immunotherapy, vol. 59, no. 1, pp. 35–46, 2010. View at Publisher · View at Google Scholar · View at Scopus
  116. M. Nourizadeh, F. Masoumi, A. Memarian, K. Alimoghaddam, S. M. Moazzeni, and J. Hadjati, “Synergistic effect of toll-like receptor 4 and 7/8 agonists is necessary to generate potent blast-derived dendritic cellsin acute myeloid leukemia,” Leukemia Research, vol. 36, no. 9, pp. 1193–1199, 2012. View at Publisher · View at Google Scholar · View at Scopus
  117. M. Nourizadeh, F. Masoumi, A. Memarian et al., “In vitro induction of potent tumor-specific cytotoxic T lymphocytes using TLR agonist-activated AML-DC,” Targeted Oncology, vol. 9, no. 3, pp. 225–237, 2014. View at Publisher · View at Google Scholar · View at Scopus
  118. R. Zhong, H. Li, K. Messer, T. A. Lane, J. Zhou, and E. D. Ball, “Augmentation of autologous T cell reactivity with acute myeloid leukemia (AML) blasts by toll-like receptor (TLR) agonists,” Cancer Immunology, Immunotherapy, vol. 64, no. 6, pp. 737–744, 2015. View at Publisher · View at Google Scholar · View at Scopus
  119. B. J. Weigel, S. Cooley, T. DeFor et al., “Prolonged subcutaneous administration of 852A, a novel systemic toll-like receptor 7 agonist, to activate innate immune responses in patients with advanced hematologic malignancies,” American Journal of Hematology, vol. 87, no. 10, pp. 953–956, 2012. View at Publisher · View at Google Scholar · View at Scopus
  120. S. L. Poh and Y. C. Linn, “Immune checkpoint inhibitors enhance cytotoxicity of cytokine-induced killer cells against human myeloid leukaemic blasts,” Cancer Immunology, Immunotherapy, vol. 65, no. 5, pp. 525–536, 2016. View at Publisher · View at Google Scholar · View at Scopus
  121. T. A. Braciak, S. Wildenhain, C. C. Roskopf et al., “NK cells from an AML patient have recovered in remission and reached comparable cytolytic activity to that of a healthy monozygotic twin mediated by the single-chain triplebody SPM-2,” Journal of Translational Medicine, vol. 11, p. 289, 2013. View at Publisher · View at Google Scholar · View at Scopus
  122. H. Bao and D. Wu, “Current status of leukemia cytotherapy-exploitation with immune cells,” Current Stem Cell Research & Therapy, vol. 12, no. 3, pp. 188–196, 2017. View at Publisher · View at Google Scholar
  123. R. J. Orlowski, D. L. Porter, and N. V. Frey, “The promise of chimeric antigen receptor T cells (CARTs) in leukaemia,” British Journal of Haematology, vol. 177, no. 1, pp. 13–26, 2017. View at Publisher · View at Google Scholar · View at Scopus
  124. X. D. Mo, X. H. Zhang, L. P. Xu et al., “Comparison of outcomes after donor lymphocyte infusion with or without prior chemotherapy for minimal residual disease in acute leukemia/myelodysplastic syndrome after allogeneic hematopoietic stem cell transplantation,” Annals of Hematology, vol. 96, no. 5, pp. 829–838, 2017. View at Publisher · View at Google Scholar
  125. M. Stahl and A. M. Zeidan, “Lenalidomide use in myelodysplastic syndromes: insights into the biologic mechanisms and clinical applications,” Cancer, vol. 123, no. 10, pp. 1703–1713, 2017. View at Publisher · View at Google Scholar
  126. C. M. Aanei, F. Z. Eloae, P. Flandrin-Gresta et al., “Focal adhesion protein abnormalities in myelodysplastic mesenchymal stromal cells,” Experimental Cell Research, vol. 317, no. 18, pp. 2616–2629, 2011. View at Publisher · View at Google Scholar · View at Scopus
  127. W. He, X. Ye, X. Huang et al., “Hsp90 inhibitor, BIIB021, induces apoptosis and autophagy by regulating mTOR-Ulk1 pathway in imatinib-sensitive and -resistant chronic myeloid leukemia cells,” International Journal of Oncology, vol. 48, no. 4, pp. 1710–1720, 2016. View at Publisher · View at Google Scholar · View at Scopus
  128. O. H. Krämer, S. Mahboobi, and A. Sellmer, “Drugging the HDAC6-HSP90 interplay in malignant cells,” Trends in Pharmacological Sciences, vol. 35, no. 10, pp. 501–509, 2014. View at Publisher · View at Google Scholar · View at Scopus
  129. D. S. Krause, T. R. Spitzer, and C. P. Stowell, “The concentration of CD44 is increased in hematopoietic stem cell grafts of patients with acute myeloid leukemia, plasma cell myeloma, and non-Hodgkin lymphoma,” Archives of Pathology & Laboratory Medicine, vol. 134, no. 7, pp. 1033–1038, 2010. View at Google Scholar
  130. X. Huang, D. Li, T. Li, B. O. Zhao, and X. Chen, “Prognostic value of the expression of phosphatase and tensin homolog and CD44 in elderly patients with refractory acute myeloid leukemia,” Oncology Letters, vol. 10, no. 1, pp. 103–110, 2015. View at Publisher · View at Google Scholar · View at Scopus
  131. J. Li, J. Yang, J. Yuan et al., “Effect of anti-CD44 monoclonal antibody A3D8 on expression of AP-1 in HL-60 cells,” Zhongguo Shi Yan Xue Ye Xue Za Zhi, vol. 24, no. 5, pp. 1360–1364, 2016. View at Google Scholar
  132. P. Chen, H. Huang, J. Wu et al., “Bone marrow stromal cells protect acute myeloid leukemia cells from anti-CD44 therapy partly through regulating PI3K/Akt-p27(Kip1) axis,” Molecular Carcinogenesis, vol. 54, no. 12, pp. 1678–1685, 2015. View at Publisher · View at Google Scholar · View at Scopus
  133. M. Casucci, B. Nicolis di Robilant, L. Falcone et al., “CD44v6-targeted T cells mediate potent antitumor effects against acute myeloid leukemia and multiple myeloma,” Blood, vol. 122, no. 20, pp. 3461–3472, 2013. View at Publisher · View at Google Scholar
  134. “ClinicalTrials.Gov,” April 2016, https://clinicaltrials.gov/ct2/show/NCT02254018.
  135. K. Andra, B. Nikolic, M. Stocher, D. Drenckhahn, and G. Wiche, “Not just scaffolding: plectin regulates actin dynamics in cultured cells,” Genes & Development, vol. 12, no. 21, pp. 3442–3451, 1998. View at Google Scholar
  136. M. H. Bae, S. H. Oh, C. J. Park et al., “VLA-4 and CXCR4 expression levels show contrasting prognostic impact (favorable and unfavorable, respectively) in acute myeloid leukemia,” Annals of Hematology, vol. 94, no. 10, pp. 1631–1638, 2015. View at Publisher · View at Google Scholar · View at Scopus
  137. B. S. Cho, Z. Zeng, H. Mu et al., “Antileukemia activity of the novel peptidic CXCR4 antagonist LY2510924 as monotherapy and in combination with chemotherapy,” Blood, vol. 126, no. 2, pp. 222–232, 2015. View at Publisher · View at Google Scholar · View at Scopus
  138. M. R. Kuhne, T. Mulvey, B. Belanger et al., “BMS-936564/MDX-1338: a fully human anti-CXCR4 antibody induces apoptosis in vitro and shows antitumor activity in vivo in hematologic malignancies,” Clinical Cancer Research, vol. 19, no. 2, pp. 357–366, 2013. View at Publisher · View at Google Scholar · View at Scopus
  139. B. Landry, H. Gul-Uludag, S. Plianwong et al., “Targeting CXCR4/SDF-1 axis by lipopolymer complexes of siRNA in acute myeloid leukemia,” Journal of Controlled Release, vol. 224, pp. 8–21, 2016. View at Publisher · View at Google Scholar · View at Scopus
  140. S. B. Peng, X. Zhang, D. Paul et al., “Inhibition of CXCR4 by LY2624587, a fully humanized anti-CXCR4 antibody induces apoptosis of hematologic malignancies,” PLoS One, vol. 11, no. 3, article e0150585, 2016. View at Google Scholar
  141. G. Z. Pan, F. X. Zhai, Y. Lu et al., “RUNX3 plays an important role in As2O3-induced apoptosis and allows cells to overcome MSC-mediated drug resistance,” Oncology Reports, vol. 36, no. 4, pp. 1927–1938, 2016. View at Publisher · View at Google Scholar · View at Scopus
  142. K. Naka, K. Ishihara, Y. Jomen et al., “Novel oral transforming growth factor-βsignaling inhibitor EW-7197 eradicates CML-initiating cells,” Cancer Science, vol. 107, no. 2, pp. 140–148, 2016. View at Publisher · View at Google Scholar · View at Scopus
  143. S. Daneshmandi, M. H. Karimi, and A. A. Pourfathollah, “TGF-β1 transduced mesenchymal stem cells have profound modulatory effects on DCs and T cells,” Iranian Journal of Immunology, vol. 14, no. 1, pp. 13–23, 2017. View at Google Scholar
  144. E. Masala, A. Valencia, F. Buchi et al., “Hypermethylation of Wnt antagonist gene promoters and activation of Wnt pathway in myelodysplastic marrow cells,” Leukemia Research, vol. 36, no. 10, pp. 1290–1295, 2012. View at Publisher · View at Google Scholar · View at Scopus
  145. A. Ghasemi, S. Rostami, B. Chahardouli, G. N. Alizad, A. Ghotaslou, and F. Nadali, “Study of SFRP1 and SFRP2 methylation status in patients with de novo acute myeloblastic leukemia,” International Journal of Hematology-Oncology and Stem Cell Research, vol. 9, no. 1, pp. 15–21, 2015. View at Google Scholar
  146. V. Martín, A. Valencia, X. Agirre et al., “Epigenetic regulation of the non - canonical Wnt pathway in acute myeloid leukemia,” Cancer Science, vol. 101, no. 2, pp. 425–432, 2010. View at Publisher · View at Google Scholar · View at Scopus
  147. K. Li, C. Hu, C. Mei et al., “Sequential combination of decitabine and idarubicin synergistically enhances anti-leukemia effect followed by demethylating Wnt pathway inhibitor promoters and downregulating Wnt pathway nuclear target,” Journal of Translational Medicine, vol. 12, p. 167, 2014. View at Publisher · View at Google Scholar · View at Scopus
  148. F. Norozi, A. Ahmadzadeh, M. Shahjahani, S. Shahrabi, and N. Saki, “Twist as a new prognostic marker in hematological malignancies,” Clinical & Translational Oncology, vol. 18, no. 2, pp. 113–124, 2016. View at Publisher · View at Google Scholar · View at Scopus
  149. A. Raval, D. M. Lucas, J. J. Matkovic et al., “TWIST2 demonstrates differential methylation in immunoglobulin variable heavy chain mutated and unmutated chronic lymphocytic leukemia,” Journal of Clinical Oncology, vol. 23, no. 17, pp. 3877–3885, 2005. View at Publisher · View at Google Scholar · View at Scopus