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CD34+ Cells in Normal and CML

Biological effects of stroma-derived factor-1α on normal and CML CD34+ haemopoietic cells

Leukemia volume 14, pages 1652–1660 (2000)Cite this article

Abstract

We compared the biological effects of the CXC chemokine SDF-1α on immunomagnetically purified CD34+ cells isolated from human normal bone marrow (NBM), leukapheresis products (LP) and patients with chronic myeloid leukaemia (CML). LP CD34+ cells showed a significantly stronger migration response to SDF-1α (100 ng/ml) than CD34+ cells isolated from the peripheral blood (PB) of CML patients (P < 0.05). the chemotactic response to sdf-1α was also reduced in cml bm cd34+ cells in comparison to NBM CD34+ cells but the observed differences were not statistically significant. In analogy to normal CD34+cells circulating CML PB CD34+ cells were less responsive to SDF-1α than their BM counterparts (P < 0.05). furthermore, sdf-1α elicited similar concentration-dependent growth suppressive effects on normal and cml cd34+cells (P > 0.05) in colony-forming cell assays. We then demonstrated that SDF-1α triggers intracellular calcium increases in CD34+ cells and there were no differences in the time course and dose response characteristics of normal and CML CD34+ cells. The reduced migration response to SDF-1α in CML CD34+ cells was not due to a down-regulation of the SDF-1α receptor CXCR-4 as flow cytometric analysis revealed similar CXCR-4 expression levels on NBM, LP, CML PB and CML BM CD34+cells (P > 0.05). Finally, no differences in the modulation of CXCR-4 levels in response to SDF-1α and serum were observed in CML and normal CD34+ cells. Our data suggest that the impaired chemotactic response of CML CD34+ cells to SDF-1α is not caused by a lack or complete uncoupling of CXCR-4, but may be due to an intracellular signalling defect downstream of the receptor. Leukemia (2000) 14, 1652–1660.

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References

  1. Broxmeyer HE, Kim CH . Regulation of hematopoiesis in a sea of chemokine family members with a plethora of redundant activities Exp Hematol 1999 27: 1113–1123

    Article  CAS  PubMed  Google Scholar 

  2. Luster AD . Chemokines-chemotactic cytokines that mediate inflammation New Engl J Med 1998 338: 436–445

    Article  CAS  PubMed  Google Scholar 

  3. Rollins BJ . Chemokines Blood 1997 90: 909–928

    CAS  PubMed  Google Scholar 

  4. Luster AD, Leder P . IP-10, a CXC chemokine, elicits a potent thymus-dependent antitumor response in vivo J Exp Med 1993 178: 1057–1065

    Article  CAS  PubMed  Google Scholar 

  5. Polentarutti N, Introna M, Sozzani S, Mancinelli R, Mantovani G, Mantovani A . Expression of monocyte chemotactic protein-3 in human monocytes and endothelial cells Eur Cytokine Netw 1997 8: 271–274

    CAS  PubMed  Google Scholar 

  6. Lukacs NW, Strieter RM, Elner VM, Evanoff HL, Burdick M, Kunkel SL . Intercellular adhesion molecule-1 mediates the expression of monocyte-derived MIP-1 alpha during monocyte–endothelial cell interactions Blood 1994 83: 1174–1178

    CAS  PubMed  Google Scholar 

  7. Sensebe L, Deschaseaux M, Li J, Herve P, Charbord P . The broad spectrum of cytokine gene expression by myoid cells from the human marrow microenvironment Stem Cells 1997 15: 133–143

    Article  CAS  PubMed  Google Scholar 

  8. Baggiolini M, Dewald B, Moser B . Interleukin-8 and related chemotactic cytokines – CXC and CC chemokines Adv Immunol 1994 55: 97–179

    Article  CAS  PubMed  Google Scholar 

  9. Baggiolini M . Chemokines and leukocyte traffic Nature 1998 392: 565–568

    Article  CAS  PubMed  Google Scholar 

  10. Kim CH, Broxmeyer HE . Chemokines: signal lamps for trafficking of T and B cells for development and effector function J Leukoc Biol 1999 65: 6–15

    Article  CAS  PubMed  Google Scholar 

  11. Koch AE, Polverini PJ, Kunkel SL et al. Interleukin-8 as a macrophage-derived mediator of angiogenesis Science 1992 258: 1798–1801

    Article  CAS  PubMed  Google Scholar 

  12. Strieter RM, Polverini PJ, Arenberg DA et al. Role of C-X-C chemokines as regulators of angiogenesis in lung cancer J Leukoc Biol 1995 57: 752–762

    Article  CAS  PubMed  Google Scholar 

  13. Tachibana K, Hirota S, Lizasa H et al. The chemokine receptor CXCR4 is essential for vascularization of the gastrointestinal tract (see comments) Nature 1998 393: 591–594

    Article  CAS  PubMed  Google Scholar 

  14. Maze R, Sherry B, Kwon BS, Cerami A, Broxmeyer HE . Myelosuppressive effects in vivo of purified recombinant murine macrophage inflammatory protein-1 alpha J Immunol 1992 149: 1004–1009

    CAS  PubMed  Google Scholar 

  15. Lord BI, Dexter TM, Clements JM, Hunter MA, Gearing AJ . Macrophage-inflammatory protein protects multipotent hematopoietic cells from the cytotoxic effects of hydroxyurea in vivo Blood 1992 79: 2605–2609

    CAS  PubMed  Google Scholar 

  16. Dunlop DJ, Wright EG, Lorimore S et al. Demonstration of stem cell inhibition and myeloprotective effects of SCI/rhMIP1 alpha in vivo Blood 1992 79: 2221–2225

    CAS  PubMed  Google Scholar 

  17. Graham GJ, Wright EG, Hewick R et al. Identification and characterization of an inhibitor of haemopoietic stem cell proliferation Nature 1990 344: 442–444

    Article  CAS  PubMed  Google Scholar 

  18. Broxmeyer HE, Sherry B, Cooper S et al. Comparative analysis of the human macrophage inflammatory protein family of cytokines (chemokines) on proliferation of human myeloid progenitor cells. Interacting effects involving suppression, synergistic suppression, and blocking of suppression J Immunol 1993 150: 3448–3458

    CAS  PubMed  Google Scholar 

  19. Dürig J, Testa NG, Heyworth CM . Distinct biological effects of macrophage inflammatory protein-1alpha and stroma-derived factor-1alpha on CD34+ hemopoietic cells Stem Cells 1999 17: 62–71

    Article  PubMed  Google Scholar 

  20. Nagasawa T, Kikutani H, Kishimoto T . Molecular cloning and structure of a pre-B-cell growth-stimulating factor Proc Natl Acad Sci USA 1994 91: 2305–2309

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Nagasawa T, Nakajima T, Tachibana K et al. Molecular cloning and characterization of a murine pre-B-cell growth-stimulating factor/stromal cell-derived factor 1 receptor, a murine homolog of the human immunodeficiency virus 1 entry coreceptor fusin Proc Natl Acad Sci USA 1996 93: 14726–14729

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Nagasawa T, Tachibana K, Kishimoto T . A novel CXC chemokine PBSF/SDF-1 and its receptor CXCR4: their functions in development, hematopoiesis and HIV infection Semin Immunol 1998 10: 179–185

    Article  CAS  PubMed  Google Scholar 

  23. Aiuti A, Tavian M, Cipponi A et al. Expression of CXCR4, the receptor for stromal cell-derived factor-1 on fetal and adult human lympho-hematopoietic progenitors Eur J Immunol 1999 29: 1823–1831

    Article  CAS  PubMed  Google Scholar 

  24. Bleul CC, Wu L, Hoxie JA, Springer TA, Mackay CR . The HIV coreceptors CXCR4 and CCR5 are differentially expressed and regulated on human T lymphocytes (see comments) Proc Natl Acad Sci USA 1997 94: 1925–1930

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Gupta SK, Pillarisetti K, Lysko PG . Modulation of CXCR4 expression and SDF-1alpha functional activity during differentiation of human monocytes and macrophages J Leukoc Biol 1999 66: 135–143

    Article  CAS  PubMed  Google Scholar 

  26. Peled A, Petit I, Kollet O et al. Dependence of human stem cell engraftment and repopulation of NOD/SCID mice on CXCR4 Science 1999 283: 845–848

    Article  CAS  PubMed  Google Scholar 

  27. Nagasawa T, Hirota S, Tachibana K et al. Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1 Nature 1996 382: 635–638

    Article  CAS  PubMed  Google Scholar 

  28. Ma Q, Jones D, Borghesani PR et al. Impaired B-lymphopoiesis, myelopoiesis, and derailed cerebellar neuron migration in CXCR4- and SDF-1-deficient mice Proc Natl Acad Sci USA 1998 95: 9448–9453

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Heveker N, Montes M, Germeroth L et al. Dissociation of the signalling and antiviral properties of SDF-1-derived small peptides Curr Biol 1998 8: 369–376

    Article  CAS  PubMed  Google Scholar 

  30. Vicente-Manzanares M, Rey M, Jones DR et al. Involvement of phosphatidylinositol 3-kinase in stromal cell-derived factor-1 alpha-induced lymphocyte polarization and chemotaxis J Immunol 1999 163: 4001–4012

    CAS  PubMed  Google Scholar 

  31. Dürig J, Chang J, Kasper C et al. Differential responsiveness of CML and normal haemopoietic progenitor cells to macrophage inflammatory protein-1 alpha (MIP-1α) Br J Haematol 1998 101: (Suppl. 1) 60, 152 (Abstr.)

    Google Scholar 

  32. Chasty RC, Lucas GS, Owen Lynch PJ, Pierce A, Whetton AD . Macrophage inflammatory protein-1 alpha receptors are present on cells enriched for CD34 expression from patients with chronic myeloid leukemia Blood 1995 86: 4270–4277

    CAS  PubMed  Google Scholar 

  33. Eaves CJ, Cashman JD, Wolpe SD, Eaves AC . Unresponsiveness of primitive chronic myeloid leukemia cells to macrophage inflammatory protein 1 alpha, an inhibitor of primitive normal hematopoietic cells Proc Natl Acad Sci USA 1993 90: 12015–12019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Dexter TM, Chang J . New strategies for the treatment of chronic myeloid leukemia Blood 1994 84: 673–675

    CAS  PubMed  Google Scholar 

  35. Dürig J, Testa NG, Lord BI et al. Characterisation of the differential response of normal and CML haemopoietic progenitor cells to macrophage inflammatory protein-1alpha Leukemia 1999 13: 2012–2022

    Article  PubMed  Google Scholar 

  36. Salgia R, Quackenbush E, Lin J et al. The bcr/abl oncogene alters the chemotactic response to stromal-derived factor-1alpha Blood 1999 94: 4233–4246

    CAS  PubMed  Google Scholar 

  37. Kim CH, Broxmeyer HE . In vitro behavior of hematopoietic progenitor cells under the influence of chemoattractants: stromal cell-derived factor-1, steel factor, and the bone marrow environment Blood 1998 91: 100–110

    CAS  PubMed  Google Scholar 

  38. Coutinho LH, Gilleece MH, de Wynter EA, Will A, Testa NG . Clonal and longterm cultures using human bone marrow. In: Testa NG, Molineux G (eds) Haemopoiesis: a Practical Approach Oxford: IRL Press 1993 75–106

    Google Scholar 

  39. Thijsen SF, Schuurhuis GJ, van Oostveen JW, Theijsmeijer AP, Langenhuijsen MM, Ossenkoppele GJ . Molecular analysis of hematopoietic colonies derived from chronic myeloid leukemia patients: interphase fluorescence in situ hybridization compared with RT-PCR Leukemia 1997 11: 301–305

    Article  CAS  PubMed  Google Scholar 

  40. Aiuti A, Webb IJ, Bleul C, Springer T, Gutierrez-Ramos JC . The chemokine SDF-1 is a chemoattractant for human CD34+ hematopoietic progenitor cells and provides a new mechanism to explain the mobilization of CD34+ progenitors to peripheral blood J Exp Med 1997 185: 111–120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Bhatia R, Munthe HA, Verfaillie CM . Role of abnormal integrin-cytoskeletal interactions in impaired β1 integrin function in chronic myelogenous leukemia hematopoietic progenitors Exp Hematol 1999 27: 1384–1396

    Article  CAS  PubMed  Google Scholar 

  42. Bhatia R, McGlave PB, Dewald GW, Blazar BR, Verfaillie CM . Abnormal function of the bone marrow microenvironment in chronic myelogenous leukemia: role of malignant stromal macrophages Blood 1995 85: 3636–3645

    CAS  PubMed  Google Scholar 

  43. Sanchez X, Cousins-Hodges B, Aguilar T, Gosselink P, Lu Z, Navarro J . Activation of HIV-1 coreceptor (CXCR4) mediates myelosuppression J Biol Chem 1997 272: 27529–27531

    Article  CAS  PubMed  Google Scholar 

  44. Cashman JD, Clark-Lewis I, Eaves CJ . SDF-1 inhibits human HPP-CFC and LTIC-proliferation in vitro and in NOD/SID mice J Exp Hematol 1999 27: 243 (Abstr.)

    Google Scholar 

  45. Broxmeyer HE, Kim CH, Cooper SH, Hangoc G, Hromas R, Pelus LM . Effects of CC, CXC, C, and CX3C chemokines on proliferation of myeloid progenitor cells, and insights into SDF-1-induced chemotaxis of progenitors Ann NY Acad Sci 1999 872: 142–162; discussion 163

    Article  CAS  PubMed  Google Scholar 

  46. Lataillade J-J, Denis C, Dupuy C et al. Chemokine SDF-1 enhances circulating CD34+ cell proliferation in synergy with cytokines: possible role in progenitor survival Blood 2000 95: 756–768

    CAS  PubMed  Google Scholar 

  47. Hodohara K, Fujii N, Yamamoto N, Kaushansky K . Stromal cell-derived factor-1 (SDF-1) acts together with thrombopoietin to enhance the development of megakaryocytic progenitor cells (CFU-MK) Blood 2000 95: 769–775

    CAS  PubMed  Google Scholar 

  48. de Wynter EA, Dürig J, Cross MA, Heyworth CM, Testa NG . Differential response of CD34+ cells isolated from cord blood and bone marrow to MIP-1α and the expression of MIP-1α receptors on these immature cells Stem Cells 1998 16: 349–356

    Article  CAS  PubMed  Google Scholar 

  49. Vaddi K, Keller M, Newton RC . The Chemokine Factsbook Academic Press: San Diego, CA 1997

    Google Scholar 

  50. Myers CD, Katz FE, Millar JL . A cell line secreting stimulating factors for CFU-GEMM culture Blood 1984 64: 152–155

    CAS  PubMed  Google Scholar 

  51. Mohle R, Bautz F, Rafii S, Moore MA, Brugger W, Kanz L . The chemokine receptor CXCR-4 is expressed on CD34+ hematopoietic progenitors and leukemic cells and mediates transendothelial migration induced by stromal cell-derived factor-1 Blood 1998 91: 4523–4530

    CAS  PubMed  Google Scholar 

  52. Honczarenko M, Douglas RS, Mathias C, Lee B, Ratajczak MZ, Silberstein LE . SDF-1 responsiveness does not correlate with CXCR4 expression levels of developing human bone marrow B cells Blood 1999 94: 2990–2998

    CAS  PubMed  Google Scholar 

  53. Andrews DFD, Collins SJ . Heterogeneity in expression of the bcr-abl fusion transcript in CML blast crisis Leukemia 1987 1: 718–724

    CAS  PubMed  Google Scholar 

  54. Gaiger A, Henn T, Horth E et al. Increase of bcr-abl chimeric mRNA expression in tumor cells of patients with chronic myeloid leukemia precedes disease progression Blood 1995 86: 2371–2378

    CAS  PubMed  Google Scholar 

  55. Signoret N, Oldridge J, Pelchen-Matthews A et al. Phorbol esters and SDF-1 induce rapid endocytosis and down modulation of the chemokine receptor CXCR4 J Cell Biol 1997 139: 651–654

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Signoret N, Rosenkilde MM, Klasse PJ et al. Differential regulation of CXCR4 and CCR5 endocytosis J Cell Sci 1998 111: 2819–2830

    CAS  PubMed  Google Scholar 

  57. Abbal C, Jourdan P, Hori T, Bousquet J, Yssel H, Pene J . TCR-mediated activation of allergen-specific CD45RO(+) memory T lymphocytes results in down-regulation of cell-surface CXCR4 expression and a strongly reduced capacity to migrate in response to stromal cell-derived factor-1 Int Immunol 1999 11: 1451–1462

    Article  CAS  PubMed  Google Scholar 

  58. Peacock JW, Jirik FR . TCR activation inhibits chemotaxis toward stromal cell-derived factor-1: evidence for reciprocal regulation between CXCR4 and the TCR J Immunol 1999 162: 215–223

    CAS  PubMed  Google Scholar 

  59. Guinamard R, Signoret N, Masamichi I, Marsh M, Kurosaki T, Ravetch JV . B cell antigen receptor engagement inhibits stromal cell-derived factor (SDF)-1alpha chemotaxis and promotes protein kinase C (PKC)-induced internalization of CXCR4 J Exp Med 1999 189: 1461–1466

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Wang JF, Park IW, Groopman JE . Stromal cell-derived factor-1 stimulates tyrosine phosphorylation of multiple focal adhesion proteins and induces migration of hematopoietic progenitor cells: roles of phosphoinositide-3 kinase and protein kinase C Blood 2000 95: 2505–2513

    CAS  PubMed  Google Scholar 

  61. Kim CH, Qu CK, Hangoc G et al. Abnormal chemokine-induced responses of immature and mature hematopoietic cells from motheaten mice implicate the protein tyrosine phosphatase SHP-1 in chemokine responses J Exp Med 1999 190: 681–690

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Haribabu B, Richardson RM, Fisher I et al. Regulation of human chemokine receptors CXCR4. Role of phosphorylation in desensitization and internalization J Biol Chem 1997 272: 28726–28731

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Ms Ute Schmücker and Mr J Barry for excellent technical assistance with flow cytometry. This work was supported by a grant from the Deutsche Forschungsgemeinschaft (SFB 545/B5). CR was supported by the Carreras Foundation.

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Authors and Affiliations

  1. Department of Haematology, University Hospital Essen, Germany

    J Dürig, C Rosenthal, K Halfmeyer, C Kasper, J Novotny & U Dührsen

  2. Department of Bone Marrow Transplantation, University Hospital Essen, Germany

    A Elmaagacli

  3. Department of Experimental Haematology, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester, UK

    C Heyworth

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Dürig, J., Rosenthal, C., Elmaagacli, A. et al. Biological effects of stroma-derived factor-1α on normal and CML CD34+ haemopoietic cells. Leukemia 14, 1652–1660 (2000). https://doi.org/10.1038/sj.leu.2401875

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