Н.Ю. Семенова, С.С. Бессмельцев, В.И. Ругаль

ФГБУ «Российский научно-исследовательский институт гематологии и трансфузиологии» ФМБА РФ, 2-я Советская ул., д. 16, Санкт-Петербург, Российская Федерация, 191024

Для переписки: С.С. Бессмельцев, д-р мед. наук, профессор, 2-я Советская ул., д. 16, Санкт-Петербург, Российская Федерация, 191024; тел.: +7(812)717-67-80; e-mail: bsshem@hotmail.com

Для цитирования: Семенова Н.Ю., Бессмельцев С.С., Ругаль В.И. Биология ниши гемопоэтических стволовых клеток. Клин. онкогематол. 2014; 7(4): 501–510.

РЕФЕРАТ

В статье представлены современные данные о роли стромальной ниши костного мозга в регуляции гемопоэтических стволовых клеток (ГСК). Отражены этапы формирования концепции гемопоэтической ниши. Дана характеристика стромальных клеточных элементов, образующих нишу, и освещены механизмы регуляции ГСК. Обсуждаются вопросы роли ниши в лейкозной трансформации ГСК. Представлены сведения о структурных изменениях ниши при нарушении развития ГСК.

Ключевые слова: гемопоэтические стволовые клетки, костный мозг, ниша гемопоэтических стволовых клеток, микроокружение.

Принято в печать: 1 сентября 2014 г.

Читать статью в PDF

ЛИТЕРАТУРА

1. Schofield R. The relationship between the spleen colony-forming cell and the haemopoietic stem cell. Blood Cells. 1978; 4: 7–25.
2. Пальцев М.А., Терских В.В., Васильев А.В. Что есть стволовая клетка. В кн.: Биология стволовых клеток и клеточные технологии. Под ред. М.А. Паль цева. Т. 1. М.: Медицина, Шико, 2009: 13–31. [Pal’tsev M.A., Terskikh V.V., Vasil’ev A.V. What is stem cell? In: Pal’tsev M.A., ed. Biologiya stvolovykh kletok i kletochnye tekhnologii. (Biology of stem cells and cell technologies.) Vol. 1. Moscow: Meditsina Publ., Shiko Publ.; 2009. pp. 13–31. (In Russ.)]
3. O’Malley D.P., Kim Y.S., Perkins S.L. et al. Morphologic and immunohistochemical evaluation of splenic hematopoietic proliferations in neoplastic and benign disorders. Mod. Pathol. 2005; 18: 1550–61.
4. Weiss L. A. Scanning electron microscopic study of the spleen. Blood. 1974; 43: 665–91.
5. Kricun M.E. Red-yellow marrow conversion: its effect on the location of some solitary bone lesions. Skeletal Radiol. 1985; 14: 10–9.
6. Williams W., Nelson D.A. Examination of the marrow. In: Hematology Williams. Ed. by E. Beulter, M.A. Lichtman et al. New York: McGraw-Hill, 1995: 15–22.
7. Bradford G.B., Williams B., Rossi R., Bertoncello I. Quiescence, cycling, and turnover in the primitive hematopoietic stem cell compartment. Exp. Hematol. 1997; 25: 445–53.
8. Lichtman M.A. The ultrastructure of the hemopoietic environment of the marrow: a review. Exp. Hematol. 1981; 9: 391–410.
9. Trentin J.J. Determination of bone marrow stem cell differentiation by stromal hemopoietic inductive microenvironments (HIM). Am. J. Pathol. 1971; 65: 621–8.
10. Wolf N.S., Trentin J.J. Hemopoietic colony studies: V. Effect of hemopoietic organ stroma on differentiation of pluripotent stem cells. J. Exp. Med. 1968; 127: 205–14.
11. Avecilla S.T., Hattori K., Heissig B. et al. Chemokine-mediated interaction of hematopoietic progenitors with the bone marrow vascular niche is required for thrombopoiesis. Nat. Med. 2004; 10: 64–71.
12. Tokoyoda K., Egawa T., Sugiyama T. et al. Cellular niches controlling B lymphocyte behavior within bone marrow during development. Immunity. 2004; 20: 707–18.
13. Dexter T.M., Allen T.D., Lajtha et al. Stimulation of differentiation and proliferation of haemopoietic cells in vitro. J. Cell Physiol. 1973; 82: 461–73.
14. Dexter T.M., Allen T.D., Lajtha L.G. Conditions controlling the proliferation of haemopoietic stem cells in vitro. J. Cell Physiol. 1977; 91: 335–44.
15. Cheshier S.H., Morrison S.J., Liao X., Weissman I.L. In vivo proliferation and cell cycle kinetics of long-term self-renewing hematopoietic stem cells. Proc. Natl. Acad. Sci. USA. 1999; 96: 3120–5.
16. Calvi L.M., Adams G.B., Weibrecht K.W. et al. Osteoblastic cells regulate the haematopoietic stem cell niche. Nature. 2003; 425: 841–46.
17. Zhang J., Niu C., Ye L. et al. Identification of the haematopoietic stem cell niche and control of the niche size. Nature. 2003; 425: 836–41.
18. Kiel M.J., Yilmaz O.H., Iwashita T. et al. SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell. 2005; 121: 1109–21.
19. Nagasawa T., Omatsu Y., Sugiyama T. Control of hematopoietic stem cells by the bone marrow stromal niche: the role of reticular cells. Trends Immunol. 2011; 32(7): 315–20.
20. Martin T.J., Sims N.A. Osteoclast-derived activity in the coupling of bone formation to resorption. Trends Mol. Med. 2005; 11: 76–81.
21. Lian J.B., Stein G.S., Aubin J.E. Bone formation: maturation and functional activities of osteoblast lineage cells. In: Primer on the metabolic bone diseases and disorders of mineral metabolism. Ed. by M.J. Favus. Washington, DC: American Society for Bone and Mineral Research, 2003: 13–28.
22. Adams G.B., Martin R.P., Alley I.R. et al. Therapeutic targeting of a stem cell niche. Nat. Biotechnol. 2007; 25: 238–43.
23. Taichman R.S., Emerson S.G. Human osteoblasts support hematopoiesis through the production of granulocyte colony-stimulating factor. J. Exp. Med. 1994; 179: 1677–82.
24. Taichman R.S., Reilly M.J., Emerson S.G. Human osteoblasts support human hematopoietic progenitor cells in vitro bone marrow cultures. Blood. 1996; 87: 518–24.
25. Taichman R.S., Emerson S.G. The role of osteoblasts in the hematopoietic microenvironment. Stem Cells. 1998; 16: 7–15.
26. Taichman R.S., Reilly M.J., Emerson S.G. The hematopoietic microenvironment: osteoblasts and the hematopoietic microenvironment. Hematology. 2000; 4: 421–6.
27. Visnjic D., Kalajzic Z., Rowe D.W. et al. Hematopoiesis is severely altered in mice with an induced osteoblast deficiency. Blood. 2004; 103: 3258–64.
28. Kiel M.J., Radice G.L., Morrison S.J. Lack of evidence that hematopoietic stem cells depend on N-cadherin-mediated adhesion to osteoblasts for their maintenance. Stem Cell. 2007; 1: 204–17.
29. Arai F., Hirao A., Ohmura M. et al. Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell. 2004; 118: 149–61.
30. Wilson A., Murphy M.J., Oskarsson T. et al. C-Myc controls the balance between hematopoietic stem cell self-renewal and differentiation. Genes Dev. 2004; 18: 2747–63.
31. Yoshihara H., Arai F., Hosokawa K. et al. Thrombopoietin/MPL signaling regulates hematopoietic stem cell quiescence and interaction with the osteoblastic niche. Cell Stem Cell. 2007; 1: 685–97.
32. Fleming H.E., Janzen V., Lo Celso C. et al. Wnt-signaling in the niche enforces hematopoietic stem cell quiescence and is necessary to preserve self-renewal in vivo. Cell Stem Cell. 2008; 2: 274–83.
33. Nilsson S.K., Johnston H.M., Whitty G.A. et al. Osteopontin, a key component of the hematopoietic stem cell niche and regulator of primitive hematopoietic progenitor cells. Blood. 2005; 106: 1232–9.
34. Stier S., Ko Y., Forkert R. et al. Osteopontin is a hematopoietic stem cell niche component that negatively regulates stem cell pool size. J. Exp. Med. 2005; 201: 1781–91.
35. Adams G.B., Chabner K.T., Alley I.R. et al. Stem cell engraftment at the endosteal niche is specified by the calcium-sensing receptor. Nature. 2006; 439: 599–603.
36. Yin T., Li L. The stem cell niches in bone. J. Clin. Invest. 2006; 116: 1195–201.
37. Broxmeyer H.E., Orschell C.M., Clapp D.W. et al. Rapid mobilization of murine and human hematopoietic stem and progenitor cells with AMD3100, a CXCR4 antagonist. J. Exp. Med. 2005; 201: 1307–18.
38. Papayannopoulou T., Scadden D.T. Stem-cell ecology and stem cells in motion. Blood. 2008; 111: 3923–30.
39. 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. 2006; 25: 977–88.
40. Sipkins D.A., Wei X., Wu J.W. et al. In vivo imaging of specialized bone marrow endothelial microdomains for tumour engraftment. Nature. 2005; 435: 969–73.
41. Ругаль В.И., Семенова Н.Ю. Морфология синусоидальных сосудов гемопоэтической ниши костного мозга. В кн.: Актуальные вопросы меди- цинских морфологических дисциплин. Коллективная монография под ред. В.П. Волкова. Новосибирск: СибАК, 2014: 62–80. [Rugal’ V.I., Semenova N.Yu. Morphology of sinousoid vessels of the bonemarrow hematopoietic-stem-cell niche. In: Volkov V.P., ed. Aktual’nye voprosy meditsinskikh morfologicheskikh distsiplin. (Urgent problems of medical morphological disciplines.) Novosibirsk: SibAK Publ.; 2014. pp. 62–80. (In Russ.)]
42. Rafii S., Shapiro F., Pettengell R. et al. Human bone marrow microvascular endothelial cells support long-term proliferation and differentiation of myeloid and megakaryocytic progenitors. Blood. 1995; 86: 3353–63.
43. Li W., Johnson S.A., Shelley W.C., Yoder M.C. Hematopoietic stem cell repopulating ability can be maintained in vitro by some primary endothelial cells. Exp. Hematol. 2004; 32: 1226–37.
44. Cumano A., Godin I. Ontogeny of the hematopoietic system. Ann. Rev. Immunol. 2007; 25: 745–85.
45. Orkin S.H., Zon L.I. Hematopoiesis: an evolving paradigm for stem cell biology. Cell. 2008; 132: 631–44.
46. Orkin S.H., Zon L.I. SnapShot: hematopoiesis. Cell. 2008; 132: 712.
47. de Saint-Georges L., Miller S.C. The microcirculation of bone and marrow in the diaphysis of the rat hemopoietic long bones. Anat. Rec. 1992; 233: 169–77.
48. Narayan K., Juneja S., Garcia C. Effects of 5-fluorouracil or total-body irradiation on murine bone marrow microvasculature. Exp. Hematol. 1994; 22: 142–8.
49. Brandi M.L., Collin-Osdoby P. Vascular biology and the skeleton. J. Bone Miner. Res. 2006; 21: 183–92.
50. Maes C., Carmeliet P., Moermans K. et al. Impaired angiogenesis and endochondral bone formation in mice lacking the vascular endothelial growth factor isoforms VEGF164 and VEGF188. Mech. Dev. 2002; 111: 61–73.
51. Maes C., Kobayashi T., Kronenberg H.M. A novel transgenic mouse model to study the osteoblast lineage in vivo. Ann. N.Y. Acad. Sci. 2007; 1116: 149–64.
52. Haug J.S., He X.C., Grindley J.C. et al. N-cadherin expression level distinguishes reserved versus primed states of hematopoietic stem cells. Cell Stem Cell. 2008; 2: 367–79.
53. Wilson A., Oser G.M., Jaworski M. et al. Dormant and self-renewing hematopoietic stem cells and their niches. Ann. N.Y. Acad. Sci. 2007; 1106: 64–75.
54. Morrison S.J., Wright D.E., Weissman I.L. Cyclophosphamide/granulocyte colony-stimulating factor induces hematopoietic stem cells to proliferate prior to mobilization. Proc. Natl. Acad. Sci. USA. 1997; 94: 1908–13.
55. Randall T.D., Weissman I.L. Phenotypic and functional changes induced at the clonal level in hematopoietic stem cells after 5-fluorouracil treatment. Blood. 1997; 89: 3596–606.
56. Zhang J., Li L. Stem cell niche: microenvironment and beyond. J. Biol. Chem. 2008; 283: 9499–503.
57. Baron R. General Principles of Bone Biology. In: Primer on the metabolic bone diseases and disorders of mineral metabolism. Ed. by M.J. Favus. Washington, DC: American Society for Bone and Mineral Research, 2003: 1–8.
58. Belloni P.N., Tressler R.J. Microvascular endothelial cell heterogeneity: interactions with leukocytes and tumor cells. Cancer Metastas. Rev. 1990; 8: 353–89.
59. Afan A.M., Broome C.S., Nicholls S.E. et al. Bone marrow innervation regulates cellular retention in the murine haemopoietic system. Br. J. Haematol. 1997; 98: 569–77.
60. Katayama Y., Battista M., Kao W.M. et al. Signals from the sympathetic nervous system regulate hematopoietic stem cell egress from bone marrow. Cell. 2006; 124: 407–21.
61. Mendez-Ferrer S., Lucas D., Battista M., Frenette P.S. Haematopoietic stem cell release is regulated by circadian oscillations. Nature. 2008; 452: 442–7.
62. Calvo W., Forteza-Vila J. On the development of bone marrow innervation in new-born rats as studied with silver impregnation and electron microscopy. Am. J. Anat. 1969; 126: 355–71.
63. Calvo W., Forteza-Vila J. Schwann cells of the bone marrow. Blood. 1970; 36: 180–8.
64. Yamazaki K., Allen T.D. Ultrastructural morphometric study of efferent nerve terminals on murine bone marrow stromal cells, and the recognition of a novel anatomical unit: the «neuro-reticular complex». Am. J. Anat. 1990; 187: 261–76.
65. Spiegel A., Shivtiel S., Kalinkovich A. et al. Catecholaminergic neurotransmitters regulate migration and repopulation of immature human CD34+ cells through Wnt signaling. Nat. Immunol. 2007; 8: 1123–31.
66. Jacenko O., Roberts D.W., Campbell M.R. et al. Linking hematopoiesis to endochondral skeletogenesis through analysis of mice transgenic for collagen X. Am. J. Pathol. 2002; 160: 2019–34.
67. Walkley C.R., Olsen G.H., Dworkin S. et al. A microenvironment-induced myeloproliferative syndrome caused by retinoic acid receptor gamma deficiency. Cell. 2007; 129: 1097–110.
68. Walkley C.R., Shea J.M., Sims N.A. et al. Rb regulates interactions between hematopoietic stem cells and their bone marrow microenvironment. Cell. 2007; 129: 1081–95.
69. Iwata M., Awaya N., Graf L. et al. Human marrow stromal cells activate monocytes to secrete osteopontin, which down-regulates Notch1 gene expression in CD34+ cells. Blood. 2004; 103: 4496–502.
70. Li L., Milner L.A., Deng Y. et al. The human homolog of rat Jagged1 expressed by marrow stroma inhibits differentiation of 32D cells through interaction with Notch1. Immunity. 1998; 8: 43–55.
71. Kollet O., Dar A., Shivtiel S. et al. Osteoclasts degrade endosteal components and promote mobilization of hematopoietic progenitor cells. Nat. Med. 2006; 12: 657–64.
72. Fukuhara S., Sako K., Minami T. et al. Differential function of Tie2 at cellcell contacts and cell-substratum contacts regulated by angiopoietin-1. Nat. Cell Biol. 2008; 10: 513–26.
73. Saharinen P., Eklund L., Miettinen J. et al. Angiopoietins assemble distinct Tie2 signalling complexes in endothelial cell-cell and cell-matrix contacts. Nat. Cell Biol. 2008; 10: 527–37.
74. Ferrara N., Davis-Smyth T. The biology of vascular endothelial growth factor. Endocr. Rev. 1997; 18: 4–25.
75. Zelzer E., Olsen B.R. Multiple roles of vascular endothelial growth factor (VEGF) in skeletal development, growth, and repair. Curr. Top. Dev. Biol. 2005; 65: 169–87.
76. Sacchetti B., Funari A., Michienzi S. et al. Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment. Cell. 2007; 131: 324–36.
77. Shi S., Gronthos S. Perivascular niche of postnatal mesenchymal stem cells in human bone marrow and dental pulp. J. Bone Miner Res. 2003; 18: 696–704.
78. Duhrsen U., Hossfeld D.K. Stromal abnormalities in neoplastic bone marrow diseases. Ann. Hematol. 1996; 73: 53–70.
79. Бессмельцев С.С. Множественная миелома (патогенез, клиника, диагностика, дифференциальный диагноз). Часть 1. Клин. онкогематол. 2013; 6(3): 237–58. [Bessmel’tsev S.S. Multiple myeloma (pathogenesis, clinical features, diagnosis, differential diagnosis). Part 1. Klin. Onkogematol. 2013; 6(3): 237–58. (In Russ.)]
80. Semenova N., Bessmeltsev S., Rugal V. Nicheforming stromal elements of bone marrow and lymph nodes in CLL. Haematologica. 2014; 99(s1): 743.
81. Ругаль В.И., Бессмельцев С.С., Семенова Н.Ю. и др. Структурные особенности паренхимы и стромы костного мозга больных множественной миеломой. Биомедицинский журнал Medline.ru. 2012; 13: 515–23. [Rugal’ V.I., Bessmel’tsev S.S., Semenova N.Yu. et al. Structural features of bone marrow parenchyma and stroma in patients with multiple myeloma. Biomeditsinskii zhurnal Medline.ru. 2012; 13: 515–23. (In Russ.)]
82. Bessmeltsev S., Rugal V. Stromal microenvironment and stem cells niche in multiple myeloma. Haematologica. 2010; 95(25): 569–570.
83. Kim Y.W., Koo B.K., Jeong H.W. et al. Defective Notch activation in microenvironment leads to myeloproliferative disease. Blood. 2008; 112: 4628–38.
84. Raajimakers M.H., Mukherjee S., Guo S. et al. Bone progenitor dysfunction induces myelodysplasia and secondary leukaemia. Nature. 2010; 464: 852–7.
85. Blau O., Hofmann W.K., Baldus C.D. et al. Chromosomal aberrations in bone marrow mesenchymal stroma cells from patients with myelodysplastic syndrome and acute myeloblastic leukemia. Exp. Hematol. 2007; 35: 221–9.
86. Sala-Torra O., Hanna C., Loken M.R. et al. Evidence of donor-derived hematologic malignancies after hematopoietic stem cell transplantation. Biol. Blood Marrow Transpl. 2006; 12: 511–7.
87. Colmone A., Amorim M., Pontier A.L. et al. Leukemic cells create bone marrow niches that disrupt the behavior of normal hematopoietic progenitor cells. Science. 2008; 322: 1861–5.
88. Jin L., Hope K.J., Zhai Q. et al. Targeting of CD44 eradicates human acute myeloid leukemic stem cells. Nat. Med. 2006; 12: 1167.
89. Krause D.S., Lazarides K., von Andrian U.H., van Etten R.A. Requirement for CD44 in homing and engraftment of BCR-ABL-expressing leukemic stem cells. Nat. Med. 2006; 12: 1175–80.
90. Miyake K., Underhill C.B., Lesley J., Kincade P.W. Hyaluronate can function as a cell adhesion molecule and CD44 participates in hyaluronate recognition. J. Exp. Med. 1990; 172: 69–75.
91. Katayama Y., Hidalgo A., Chang J. et al. CD44 is a physiological Eselectin ligand on neutrophils. J. Exp. Med. 2005; 201: 1183–9.
92. Dimitroff C.J., Lee J.Y., Rafii S. et al. CD44 is a major E-selectin ligand on human hematopoietic progenitor cells. J. Cell Biol. 2001; 153: 1277–86.
93. Krause D.S., von Andrian U.H., van Etten R.A. Selectins and their ligands are required for for homing and engraftment of BCR-ABL leukemia-initiating cells. Blood. 2005; 106: 106a.
94. Jin L., Lee E.M., Ramshaw H.S. et al. Monoclonal antibody-mediated targeting of CD123, IL-3 receptor alpha chain, eliminates human acute myeloid leukemic stem cells. Cell Stem Cell. 2009; 5: 31–42.
95. Garg M., Moore H., Tobal K., Liu Yin J.A. Prognostic significance of quantitative analysis of WT1 gene transcripts by competitive reverse transcription polymerase chain reaction in acute leukaemia. Br. J. Haematol. 2003; 123: 49–59.
96. Ishikawa F., Yoshida S., Saito Y. et al. Chemotherapy-resistant human AML stem cells home to and engraft within the bone-marrow endosteal region. Nat. Biotechnol. 2007; 25: 1315–21.
97. Saito Y., Uchida N., Tanaka S. et al. Induction of cell cycle entry eliminates human leukemia stem cells in s a mouse model of AML. Nat. Biotechnol. 2010; 28: 275–80.
98. Klyuchnikov E., Kroger N. Sensitising leukemic cells by targeting microenvironment. Leuk. Lymphoma. 2009; 50: 319–20.
99. Matsunaga T., Takemoto N., Sato T. et al. Interaction between leukemiccell VLA-4 and stromal fibronectin is a decisive factor for minimal residual disease of acute myelogenous leukemia. Nat. Med. 2003; 9: 1158–65.
100. Mraz M., Zent C.S., Church A.K. et al. Bone marrow stromal cells protect lymphoma B-cells from rituximab-induced apoptosis and targeting integrin alpha-4-beta-1 (VLA-4) with natalizumab can overcome this resistance. Br. J. Haematol. 2011; 155: 53–64.
101. Vianello F., Villanova F., Tisato V. et al. Bone marrow mesenchymal stromal cells non-selectively protect chronic myeloid leukemia cells from imatinib-induced apoptosis via the CXCR4/CXCL12 axis. Haematologica. 2010; 95: 1081–9.
102. Weisberg E., Azab A.K., Manley P.W. et al. Inhibition of CXCR4 in CML cells disrupts their interaction with the bone marrow microenvironment and sensitizes them to nilotinib. Leukemia. 2012; 26: 985–90.
103. Bhatia R., McGlave P.B., Dewald G.W. et al. Abnormal function of the bone marrow microenvironment in chronic myelogenous leukemia: role of malignant stromal macrophages. Blood. 1995; 85: 3636–45.
104. Bewry N.N., Nair R.R., Emmons M.F. et al. Stat3 contributes to resistance toward BCR-ABL inhibitors in a bone marrow microenvironment model of drug resistance. Mol. Cancer Ther. 2008; 7: 3169–75.
105. Scupoli M.T., Perbellini O., Krampera M. et al. Interleukin 7 requirement for survival of T-cell acute lymphoblastic leukemia and human thymocytes on bone marrow stroma. Haematologica. 2007; 92: 264–6.
106. Yamamoto-Sugitani M., Kuroda J., Ashihara E. et al. Galectin-3 (Gal-3) induced by leukemia microenvironment promotes drug resistance and bone marrow lodgment in chronic myelogenous leukemia. Proc. Natl. Acad. Sci. USA. 2011; 108: 17468–73.
107. Lane S.W., Wang Y.J., Lo Celso C. et al. Differential niche and Wnt requirements during acute myeloid leukemia progression. Blood. 2011; 118: 2849–56.
108. Wei J., Wunderlich M., Fox C. et al. Microenvironment determines lineage fate in a human model of MLL-AF9 leukemia. Cancer Cell. 2008; 13: 483–95.
109. Spitzer T.R., Dey B.R., Chen Y.B. et al. The expanding frontier of hematopoietic cell transplantation. Cytometr. B. Clin. Cytom. 2012; 82(5): 271–9.
110. Jordan C.T., Upchurch D., Szilvassy S.J. et al. The interleukin-3 receptor alpha chain is a unique marker for human acute myelogenous leukemia stem cells. Leukemia. 2000; 14: 1777–84.
111. Kugler M., Stein C., Kellner C. et al. A recombinant trispecific singlechain Fv derivative directed against CD123 and CD33 mediates effective elimination of acute myeloid leukaemia cells by dual targeting. Br. J. Haematol. 2010; 150: 574–86.
112. Krause D.S., Fulzele K., Catic A. et al. Parathyroid hormone-induced modulation of the bone marrow microenvironment reduces leukemic stem cells in murine chronic myelogenous-leukemia-like disease via a TGFbeta-dependent pathway. Blood. 2011; 118: 1670.