hematopoietic stem cell

Role of Defects of Hematopoietic and Lymphoid Niches in Genesis of Chronic Lymphocytic Leukemia

LYMPHOID TUMORS , , , , ,

NYu Semenova, SS Bessmel’tsev, VI Rugal’

Russian Scientific Research Institute of Hematology and Transfusiology, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024

For correspondence: Natal’ya Yur’evna Semenova, PhD, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024; Tel.: +7(812)717-09-95; e-mail: sciencerugal@gmail.com

For citation: Semenova NYu, Bessmel’tsev SS, Rugal’ VI. Role of Defects of Hematopoietic and Lymphoid Niches in Genesis of Chronic Lymphocytic Leukemia. Clinical oncohematology. 2016;9(2):176–90 (In Russ).

DOI: 10.21320/2500-2139-2016-9-2-176-190

ABSTRACT

Background & Aims. Niche-forming elements of the bone marrow and lymphoid organs play an important role in the pathogenesis of chronic lymphocytic leukemias. The aim is to determine multifunctional characteristics of stromal elements of the hematopoietic and lymphoid microenvironment involved in formation of a niche of hematopoietic stem cells and lymphoid precursor cells.

Methods. Histological specimens of the bone marrow and lymph nodes of 112 CLL patients (64 men and 48 women) were investigated. 45 patients were included in the combined analysis group. The age median was 60 years. 50 volunteers were included in the control group: trepanobiopsy of the iliac area was performed in 30 healthy subjects, and lymph node biopsy was performed in 20 patients with reactive lymphadenopathy. Standard staining (hematoxylin-eosin, azure-II-eosin, silver impregnation, Masson stain) was used for histological studies. The immunohistochemical analysis was performed using the primary antibody panel and the polymer visualization system Dako according to staining protocol.

Results. While analyzing 96 trepanobioptates, we isolated three types of bone marrow infiltration: nodular (18.8 %, n = 18), interstitial (27 %, n = 26) and diffuse (54.2 %, n = 52). Nodular and interstitial bone marrow infiltrations reflect a more favorable course of CLL as compared to the diffuse type. The morphological characteristics of the bone marrow stroma of CLL patients may be caused by both primary impairment of the hematopoietic microenvironment, and cytokine disbalance resulting from the effect on the stroma of the leukemic clone. The morphological examination of lymph node bioptate of CLL patients demonstrated impairment of histoarchitectonics of lymphoid tissue elements in all cases. In lymph nodes of CLL patients, we demonstrated the increased number of small vessels on the background of decreased expression of extracellular matrix protein expression: IV type collagen, laminin, and desmin. Disintegration of lymph node follicular dendritic cells network was demonstrated.

Conclusion. Examination of the nature of the effect of stroma on hematopoiesis remains an urgent hematological problem. In order to solve the problem of regulatory influence, the use of morphological methods is recommended, including the immunohistochemical analysis.

Keywords: hematopoietic stem cell, bone marrow, hematopoietic stem cell niche, microenvironment, lymphoid niche, follicular dendritic cells.

Received: October 8, 2015

Accepted: January 10, 2016

Read in PDF (RUS)pdficon

REFERENCES

  1. Ругаль В.И. Морфофункциональная характеристика стромы костного мозга в норме и при остром миелобластном лейкозе: Автореф. дис. ¼ д-ра мед. наук. Л., 1989.
    [Rugal’ VI. Morfofunkcionalnaja harakteristika stromy kostnogo mozga v norme i pri ostrom mieloblastnom lejkoze. (Morphofunctional characteristics of the bone marrow stroma in normal persons and in patients with acute mieloblastic leukemia.) [dissertation] Leningrad; 1989. (In Russ)]
  2. Krause D, Scadden D, Preffer L. The Hematopoietic Stem Cell Niche — Home for Friend and Foe. Clin Cytometry. 2012;58(7):7–20. doi: 10.1002/cyto.b.21066.
  3. Chiorazzi N, Rai KR, Ferrarini M. Chronic lymphocytic leukemia. N Engl J Med. 2005;352(8):804–15. doi: 10.1056/nejmra041720.
  4. Rawstron AC, Bennett FL, O’Connor SJ, et al. Monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia. N Engl J Med. 2008;359(6):575–83. doi: 10.1056/NEJMoa075290.
  5. Asplund SL, McKenna RW, Howard M, Croft SH. Immunophenotype does not correlate with lymph node gistology in chronic lymphocytic leukemia/small lymphocytic lymphoma. Am J Surg Pathol. 2002;26(5):624–9. doi: 10.1097/00000478-200205000-00008.
  6. Montillo M, Hamblin T, Hallek M, et al. Chronic lymphocytic leukemia: novel prognostic factors and their relevance for risk-adapted therapeutic strategies Haematologica. 2005;90(3):391–9.
  7. Бакиров Б.А. Клинико-патогенетическая характеристика и факторы прогноза в развитии и течении хронического лимфолейкоза: Автореф. ¼ д-ра мед. наук. СПб., 2013.
    [Bakirov BA. Kliniko-patogeneticheskaja harakteristika i faktory prognoza v razvitii i techenii hronicheskogo limfoleikoza. (Clinico-pathological characteristics and prognostic factors in development and course of chronic lymphocytic leukemia.) [dissertation] Saint Petersburg; 2013. (In Russ)]
  8. Hallek M, Cheson BD, Cotovsky D, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute Working Group 1996 guidelines. Blood. 2008;111(12):544–6. doi: 10.1182/blood-2007-06-093906.
  9. Бессмельцев С.С., Абдулкадыров К.М. Флударабин в терапии различных вариантов неходжкинских лимфом. Современная онкология. 2011;13(4):13–9.
    [Bessmeltsev SS, Abdulkadirov KM. Fludarabine in treatment different variants non-Hodgkin’s lymphoma. Sovremennaya onkologiya. 2011;13(4):13–9. (In Russ)]
  10. Бессмельцев С.С. Современные методы диагностики и лечения больных хроническим лимфолейкозом. Вестник гематологии. 2011;1:137–56.
    [Bessmel’tsev SS. Modern methods of diagnosis and treatment of patients with chronic lymphocytic leukemia. Vestnik gematologii. 2011;1:137–56. (In Russ)]
  11. Семенова Н.Ю. Морфологические особенности интрамедуллярных стромальных структур гемопоэтической ниши и элементов лимфоидной стромы при хроническом лимфолейкозе: Дис. ¼ канд. биол. наук. СПб., 2015.
    [Semenova NYu. Morfologicheskie osobennosti intramedullyarnykh stromal’nykh struktur gemopoeticheskoi nishi i elementov limfoidnoi stromy pri khronicheskom limfoleikoze. (Morphological features of intramedullary stromal structures of hematopoietic niche and elements of the lymphoid stroma in chronic lymphocytic leukemia.) [dissertation] Saint Petersburg; 2015. (In Russ)]
  12. Amin S, Parker A, Manu J. Zap 70 in chronic lymphocytic leukemia. Int J Biochem Cell Biol. 2008;40(9):1654–8. doi: 10.1016/j.biocel.2007.05.016.
  13. Wolowiec D, Wozniak Z, Potoczek S. Bone marrow angiogenesis and proliferation in B-cell chronic lymphocytic leukemia. Anal Quant Cytol Histol. 2004;26(5):263–70.
  14. Чертков И.Л., Гуревич О.А. Стволовая кроветворная клетка и ее микроокружение. М., 1984. 238 с.
    [Chertkov IL, Gurevich ОА. Stvolovaya krovetvornaya kletka i ee mikrookruzhenie. (Hematopoietic stem cell and its microenvironment). Мoscow; 1984. 238 p. (In Russ)]
  15. Mayani H, Guilbert LJ, Janowaska-Wieczorek A. Biology of the hemopoietic microenvironment. Eur J Haematol. 1992;49(5):225–33. doi: 10.1111/j.1600-0609.1992.tb00053.x.
  16. Gothard D, Greenhough J, Ralph E. Prospective isolation of human bone marrow stromal cell subsets: A comparative study between Stro-1-, CD146- and CD105-enriched populations. J Tissue Eng. 2014;5(0): doi: 10.1177/2041731414551763.
  17. Purton LE, Scadden DT. The hematopoietic stem cell niche. StemBook [Internet]. Cambridge (MA): Harvard Stem Cell Institute; 2008. pp. 1–14. doi: 10.3824/stembook.1.28.1.
  18. Taichman RS, Reilly MJ, Emerson SG. The hematopoietic microenvironment: osteoblasts and the hematopoietic microenvironment. Hematology. 2000;4(5):421–6.
  19. Scadden DT. The stem cell niche in health and leukemic disease. Best Pract Res Clin Haematol. 2007;20(1):19–27. doi: 10.1016/j.beha.2006.11.001.
  20. Семенова Н.Ю., Бессмельцев С.С., Ругаль В.И. Биология ниши гемопоэтических стволовых клеток. Клиническая онкогематология. 2014;7(4):501–10.
    [Semenova NYu, Bessmel’tsev SS, Rugal’ VI. Biology of hematopoietic stem cell niche. Klinicheskaya onkogematologiya. 2014;7(4):501–10. (In Russ)]
  21. Zhang J, Li L. Stem cell niche: microenvironment and beyond. J Biol Chem. 2008;283(15):9499–503. doi: 10.1074/jbc.R700043200.
  22. Бессмельцев С.С. Множественная миелома (патогенез, клиника, диагностика, дифференциальный диагноз). Часть 1. Клиническая онкогематология. 2013;6(3):237–58.
    [Bessmeltsev SS. Multiple myeloma (pathogenesis, clinical features, diagnosis, differential diagnosis). Part I. Klinicheskaya onkogematologiya. 2013;6(3):237–58. (In Russ)]
  23. 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;13:515–523.
    [Rugal VI, Bessmeltsev SS, Semenova NYu, et al. Parenchyma and stroma bone marrow structural features in patients with multiple myeloma. Biomeditsinskii zhurnal Medline.ru. 2012;13:515–23. (In Russ)]
  24. Duhrsen U, Hossfeld DK. Stromal abnormalities in neoplastic bone marrow diseases. Ann Hematol. 1996;73(2):53–70. doi: 10.1007/s002770050203.
  25. Weisberg E, Azab AK, Manley PW, et al. Inhibition of CXCR4 in CML cells disrupts their interaction with the bone marrow microenvironment and sensitizes them to nilotinib. Leukemia. 2012;26(5):985–90. doi: 10.1038/leu.2011.360.
  26. Белянин В.Л., Цыплаков Д.Э. Диагностика реактивных гиперплазий лимфатических узлов. СПб., Казань, 1999. 328 с.
    [Belyanin VL, Tsyplakov DE. Diagnostika reaktivnykh giperplazii limfaticheskikh uzlov. (Diagnosis of reactive hyperplasia of lymph nodes.) Saint Petersburg, Kazan; 1999. 328 p. (In Russ)]
  27. Киселева М.В. Морфо-функциональное состояние стромы лимфатических узлов при некоторых лимфопролиферативных заболеваниях: Автореф. дис. ¼ канд. мед. наук. СПб., 2001.
    [Kiseleva MV. Morfo-funktsionalnoe sostoyanie stromy limfaticheskikh uzlov pri nekotoryh limfoproliferativnykh zabolevaniyah. (Morphofunctional state of the stroma of lymph nodes in certain lymphoproliferative diseases.) [dissertation] Saint Petersburg; 2001. (In Russ)]
  28. Chen L, Apgar J, Huynh L, et al. ZAP-70 directly enhances IgM signaling in chronic lymphocytic leukemia. Blood. 2005;105(5):2036–41. doi: 10.1182/blood-2004-05-1715.
  29. Коган Е.А. Автономный рост и прогрессия опухолей. Российский журнал гастроэнтерологии, гепатологии, колопроктологии. 2002;12(4):45–9.
    [Kogan EA. Autonomous growth and progression of tumors. Rossiiskii zhurnal gastroenterologii, gepatologii, koloproktologii. 2002;12(4):45–9. (In Russ)]
  30. Криволапов Ю.А., Леенман Е.Е. Морфологическая диагностика лимфом. СПб.: Коста, 2006. С. 45–8.
    [Krivolapov YuA, Leenman EE. Morfologicheskaya diagnostika limfom. (Morphological diagnostics of lymphomas.) Saint Petersburg: Kosta Publ.; 2006. pp. 45–8. (In Russ)]
  31. Мухина М.С., Пожарисский К.М., Леенман Е.Е. и др. Место дендритных клеток в микроокружении при лимфоме Ходжкина. Архив патологии. 2010;2:3–7.
    [Mukhina MS, Pozharisskii KM, Leenman EE, et al. Place of dendritic cells in the microenvironment in Hodgkin lymphoma. Arkhiv patologii. 2010;2:3–7. (In Russ)]
  32. Park CS, Choi YS. How do follicular dendritic cells interact intimately with B cells in the germinal centre. Immunology. 2005;114(1):2–10. doi: 10.1111/j.1365-2567.2004.02075.x.
  33. Herishanu Y, Perez-Galan P, Liu D, et al. The lymph node microenvironment promotes B-cell receptor signaling, NF-kappaB activation, and tumor proliferation in chronic lymphocytic leukemia. Blood. 2011;117(2):563–74. doi: 10.1182/blood-2010-05-284984.
  34. Cordone I, Matutes E, Catovsky D. Monoclonal antibody Ki-67 identifies B and T cells in cycle in chronic lymphocytic leukemia: correlation with disease activity. Leukemia. 1992;6(9):902–6.
  35. Tavassoli M, Fridenstein A. Hemopoietic stromal microenvironment. Am J Hematol. 1983;15(2):195–203. doi: 10.1002/ajh.2830150211.
  36. 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. doi: 10.1016/j.it.2011.03.009.
  37. Orkin SH, Zon LI. Hematopoiesis: an evolving paradigm for stem cell biology. Cell. 2008;132(4):631–44. doi: 10.1016/j.cell.2008.01.025.
  38. Yin T, Li L. The stem cell niches in bone. J Clin Invest. 2006;116(5):1195–201. doi: 10.1172/jci28568.
  39. Wei J, Wunderlich M, Fox C, et al. Microenvironment determines lineage fate in a human model of MLL-AF9 leukemia. Cancer Cell. 2008;13(6):483–95. doi: 10.1016/j.ccr.2008.04.020.
  40. Westen H, Beinton DF. Association of alkaline-phosphatase-positive reticulum cells in bone marrow granulocytic precursors. Exp Med. 1979;150(4):919–37. doi: 10.1084/jem.150.4.919.
  41. Taichman RS, Emerson SG. Human osteoblasts support hematopoiesis through the production of granulocyte colony-stimulating factor. J Exp Med. 1994;179(5):1677–82. doi: 10.1084/jem.179.5.1677.
  42. Zhang J, Niu C, Ye L, et al. Identification of the haematopoietic stem cell niche and control of the niche size. Nature. 2003;425(6960):836–41. doi: 10.1038/nature02041.
  43. Tokoyoda K, Egawa T, Sugiyama T, et al. Cellular niches controlling B lymphocyte behavior within bone marrow during development. Immunity. 2004;20(6):707–18. doi: 10.1016/j.immuni.2004.05.001.
  44. Дризе Н.И. Различия между лейкозными и нормальными кроветворными стволовыми клетками. Онкогематология. 2006;1(2):5–9.
    [Drize NI. Difference between leukemic and normal hematopoietic stem cells. Onkogematologiya. 2006;1(2):5–9. (In Russ)]
  45. Mraz M, Zent CS, Church AK, 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(1):53–64. doi: 10.1111/j.1365-2141.2011.08794.x.
  46. Papayannopoulou T, Scadden DT. Stem-cell ecology and stem cells in motion. Blood. 2008;111(8):3923–30. doi: 10.1182/blood-2007-08-078147.
  47. 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(3):275–80. doi: 10.1038/nbt.1607.
  48. Вартанян Н.Л., Бессмельцев С.С., Семенова Н.Ю., Ругаль В.И. Мезенхимальные стромальные клетки при апластической анемии, гемобластозах и негематологических опухолях. Бюллетень СО РАМН. 2014;34(6):17–26.
    [Vartanyan NL, Bessmel’tsev SS, Rugal’ VI, Semenova NYu. Mesenchymal stromal cells in aplastic anemia, hematological malignancies and non-hematological tumors. Byulleten’ SO RAMN. 2014;34(6):17–26. (In Russ)]
  49. Raaijmakers M, Mukherjee S, Guo SH, et al. Bone progenitor dysfunction induces myelodysplasia and leukemia. Nature. 2010;464(7290):852–7. doi: 10.1038/nature08851.
  50. Герасимова Л.П., Дризе Н.И., Лубкова О.Н. и др. Нарушение стромального микроокружения у больных с различными заболеваниями системы крови. Гематология и трансфузиология. 2008;53(5):59–62.
    [Gerasimova LP, Drize NI, Lybkova ON, et al. Stromal microenvironment impairment in patients with various hematological diseases. Gematologiya i transfuziologiya. 2008;53(5):59–62. (In Russ)]

 

Biology of Hematopoietic Stem Cell Niche

REVIEWS , , ,

N.Yu. Semenova, S.S. Bessmel’tsev, V.I. Rugal’

Russian Scientific Research Institute of Hematology and Transfusiology under the Federal Medico-Biological Agency, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024

For correspondence: S.S. Bessmel’tsev, DSci, Professor, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024; Tel: +7(812)717-67-80; e-mail: bsshem@hotmail.com

For citation: Semenova N.Yu., Bessmel’tsev S.S., Rugal’ V.I. Biology of Hematopoietic Stem Cell Niche. Klin. Onkogematol. 2014; 7(4): 501–510 (In Russ.).

ABSTRACT

The article presents up-to-date data on the role of bone marrow stromal niche in hematopoietic stem cells regulation (HSC). It describes stages of development of the hematopoietic niche concept. Characteristics of stromal cellular elements which form the niche are presented. Mechanisms of HSC regulation by the stromal niche are reported. The role of the niche in HSC leukemic transformation is discussed. It also presents data on structural changes in the niche in case of HSC development disorder.

Keywords: hematopoietic stem cell, bone marrow, hematopoietic stem cell niche, microenvironment.

Accepted: September 1, 2014

Read in PDF (RUS)pdficon

REFERENCES

  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.