Skip to main content
SpringerLink
Log in

Benign hematopoietic progenitors in chronic myeloid leukemia: Current status and future prospects

  • Review Article
  • Published:
Annals of Hematology Aims and scope Submit manuscript

Summary

Many patients with chronic myeloid leukemia (CML) retain a certain degree of normal hematopoiesis at disease presentation. This fact, suspected on the basis of cytogenetic findings, has been confirmed by long-term bone marrow cultures (LTBMC) and the combined use of phenotypic and molecular studies. Based on the lack of HLA-DR expression, it has been possible to recognize a benign subpopulation within the stem-cell compartment in CML. Different in vitro techniques have been developed for the selection of these benign progenitors, including LTBMC, marrow incubation with cytolytic drugs or interferon, positive selection based on their phenotypic characteristics, and exposure to synthetic antisense oligodeoxynucleotides. In vivo selection with interferon or intensive chemotherapy is also possible. The primary goal of the selection of benign hematopoietic progenitors is their use for autotransplantation. To date, a few hundred CML patients have been submitted to the latter procedure using bone marrow or peripheral blood. The fact that the majority of them show evidence of persistent disease emphasizes the necessity for better selection methods of the benign progenitors, for intensifying the conditioning regimen to reduce the tumor burden as much as possible, and for the use of adjuvant therapy post-transplantation. Future trends include the refinement of positive selection methods, negative selection by taking advantage of the different stromal adhesiveness of the benign and malignant progenitors, or the use of autologous natural killer cells, antisense oligodeoxynucleotides, or specific antibodies to the bcr/abl junction region, and retroviral marking to determine the origin of relapse in autologous transplantation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Agarwal R, Doren S, Hicks B, Dunbar CE (1993) Long-term culture of CML marrow on stem cell factor-deficient stroma favors benign progenitors. Blood 82 [Suppl 1]: 382a

    Google Scholar 

  2. Andrews RG, Singer JE, Berstein ID (1990) Human hematopoietic precursors in long-term culture: single CD34+ cells that lack detectable T-cell, B-cell and myeloid antigens produce multiple colony-forming cells when cultured with marrow stromal cells. J Exp Med 172:355–358

    PubMed  Google Scholar 

  3. Barnett MJ, Eaves CJ, Phillips GL et al (1989) Successful autografting in chronic myeloid leukemia after maintenance of marrow in culture. Bone Marrow Transplant 4:345–351

    PubMed  Google Scholar 

  4. Baum CM, Weissman IL, Tsukamoto AS, Buckle AM, Peault B (1992) Isolation of a candidate human hematopoietic stemcell population. Proc Natl Acad Sci USA 89:2804–2808

    PubMed  Google Scholar 

  5. Becker M, Fabrega S, Belloc F, Rice A, Barbu V, Reiffers J (1993) Interferon gamma is effective for BM purging in a patient with CML. Bone Marrow Transplant 12:155–158

    PubMed  Google Scholar 

  6. Bhatia R, Mc Glave PB, Wayner E, Verfaillie CM (1993) Interferon-α restores adhesion of CML progenitors to bone marrow stroma by correcting impaired β-1 integrin receptor function. Blood 82 [Suppl 1]:3317

    Google Scholar 

  7. Brandt L, Mitelman F, Panani A, Lenner HC (1976) Extremely long duration of chronic myeloid leukaemia with Ph' negative and Ph' positive bone marrow cells. Scand J Haematol 16:321–325

    PubMed  Google Scholar 

  8. Brito-Babapulle F, Bowcock SJ, Marcus RE et al (1989) Autografting for patients with chronic myeloid leukaemia in chronic phase: peripheral blood stem cells may have a finite capacity for maintaining haemopoiesis. Br J Haematol 73:76–81

    PubMed  Google Scholar 

  9. Buroughs J, Gupta P, Verfaillie CM (1994) Diffusible factors from the murine cell line M2-10B4 support human in vitro hematopoiesis. Exp Hematol (in press)

  10. Calabretta B (1992) In vitro and in vivo suppression of Philadelphia + leukemic growth by bcr-abl anti-sense oligodeoxynucleotides. Proceedings of the 2nd International Conference on Chronic Myeloid Leukemia. Bologna, October 1992, abstract no. 61

  11. Carella AM, Gaozza E, Raffo MR et al (1991) Therapy of acute-phase chronic myelogenous leukemia with intensive chemotherapy, blood cell autotransplant and cyclosporin A. Leukemia 5:517–521

    PubMed  Google Scholar 

  12. Carlo-Stella C, Mangoni L, Piovani G, Almici C, Garau D, Caramatti C, Rizzoli V (1991) In vitro marrow purging in chronic myelogenous leukemia: effect of mafosfamide and recombinant granulocyte-macrophage colony-stimulating factor. Bone Marrow Transplant 8:265–273

    PubMed  Google Scholar 

  13. Cashman JD, Eaves AC, Raines EW, Ross R, Eaves CJ (1990) Mechanisms that regulate the cell cycle status of very primitive hematopoietic cells in long-term human marrow cultures. I. Stimulatory role of a variety of mesenchymal cell activators and inhibitory role of TGF-B. Blood 75:96–101

    PubMed  Google Scholar 

  14. Cervantes F, Rozman C, Ballesta F, Milá M (1982) Prognostic significance of cytogenetical studies in chronic granulocytic leukaemia. Scand J Haematol 28:77–81

    PubMed  Google Scholar 

  15. Cervantes F, Robertson JE, Rozman C et al (1994) Longterm survivors in chronic granulocytic leukaemia: a study of the International CGL Prognosis Study Group. Br J Haematol 87:293–300

    PubMed  Google Scholar 

  16. Clarkson B, Strife A (1993) Linkage of proliferative and maturational abnormalities in chronic myelogenous leukemia and relevance to treatment. Leukemia 7:1683–1721

    PubMed  Google Scholar 

  17. Coulombel L, Kalousek DK, Eaves CJ, Guzta CM, Eaves AC (1993) Long-term marrow culture reveals chromosomally normal hematopoietic progenitor cells in patients with Philadelphia chromosome-positive chronic myelogenous leukemia. N Engl J Med 308:1493–1498

    Google Scholar 

  18. Daley GQ, Goldman JM (1993) Autologous transplant for CML revisited. Exp Hematol 21:734–737

    PubMed  Google Scholar 

  19. De Fabriitis P, Amadori S, Calabretta B, Mandelli F (1993) Elimination of clonogenic Philadelphia-positive cells using BRC-ABL antisense oligonucleotides. Bone Marrow Transplant 12:261–265

    PubMed  Google Scholar 

  20. Degliantoni G, Mangoni L, Rizzoli V (1985) In vitro restoration of polyclonal hematopoietis in a chronic myelogenous leukemia after in vitro treatment with 4-hydroxyperoxycyclophosphamide. Blood 65:753–757

    PubMed  Google Scholar 

  21. Deisseroth AB, Zhang W, Cha Y et al (1992) New directions in the biology and therapy of chronic myeloid leukemia. Leuk Lymph 6:89–95

    Google Scholar 

  22. Dexter TM, Allen TD, Lajtha LG (1976) Conditions controlling the proliferation of hemopoietic stem cells in vitro. J Cell Physiol 91:335–344

    Google Scholar 

  23. Dowding C, Guo A, Osterholz J, Siczkowski M, Goldman J, Gordon M (1991) Interferon-alpha overrides the deficient adhesion of chronic myeloid leukemia primitive progenitor cells to bone marrow stromal cells. Blood 78:499–505

    PubMed  Google Scholar 

  24. Dubé ID, Kalousek DK, Coulombel L, Gupta CM, Eaves CJ, Eaves AC (1984) Cytogenetic studies in early myeloid progenitor compartments in Ph′-positive chronic myeloid leukemia. II Long-term culture reveals the persistence of Ph′-negative progenitors in treated as well as newly diagnosed patients. Blood 63:1172–1177

    PubMed  Google Scholar 

  25. Dubé ID, Arlin ZA, Kalousek DK, Eaves CJ, Eaves AC (1984) Nonclonal hemopoietic progenitor cells detected in long-term marrow cultures from a Turner syndrome mosaic with chronic myeloid leukemia. Blood 64:1284–1287

    PubMed  Google Scholar 

  26. Dunbar CE, Stewart FM (1992) Separating the wheat from the chaff: selection of benign hematopoietic cells in chronic myeloid leukemia. Blood 79:1107–1110

    PubMed  Google Scholar 

  27. Eaves CJ, Barnett MJ, Eaves AC (1993) In vitro culture of bone marrow cells for autografting in CML. Leukemia 7 [Suppl 2]: 126–129

    Google Scholar 

  28. Editorial (1992) Chronic myeloid leukaemia: potential for antisense therapy. Lancet 2:1262–1263

  29. Fauser AA, Kanz L, Bross KJ, Lohr GW (1985) T cells and probably B cells arise from the malignant clone in chronic myelogenous leukemia. J Clin Invest 75:1080–1092

    PubMed  Google Scholar 

  30. Fiacchini M (1992) Prognostic study of alpha-interferon (IFN)-treated chronic myeloid leukemia (CML) patients. I. Predicting karyotypic response. Proceedings of the 2nd International Conference on Chronic Myeloid Leukemia, Bologna, October 1992, p 99

  31. Fialkow PJ, Jacobson RJ, Panayannopoulu T (1977) Chronic myelocytic leukemia: clonal origin in a stem cell common to the granulocyte, erythrocyte, platelet, and monocyte/macrophage. Am J Med 63:125–130

    PubMed  Google Scholar 

  32. Finney R, Mc Donald GA, Baikie AG, Douglas AS (1972) Chronic granulocytic leukaemia with Ph′ negative cells in bone marrow and a ten-year remission after bulsulphan hypoplasia. Br J Haematol 23:283–288

    PubMed  Google Scholar 

  33. Gale RP, Butturini A (1992) Can intensive chemotherapy cure chronic myelogenous leukemia? Leukemia 6:863–865

    PubMed  Google Scholar 

  34. Goldman JM, Gale RP, Horowitz MM et al (1988) Bone marrow transplantation for chronic myelogenous leukemia in chronic phase: increased risk of relapse associated with T-cell depletion. Ann Intern Med 108:806–814

    PubMed  Google Scholar 

  35. Goldman JM, Deisseroth AB (1992) Use of autotransplants in chronic myeloid leukemia. Bone Marrow Transplant 12:155–158

    Google Scholar 

  36. Gordon MY, Dowding CR, Riley GP, Goldman JM, Greaves MF (1987) Altered adhesive interactions with marrow stroma of haemopoietic progenitor cells in chronic myeloid leukaemia. Nature 288:342–345

    Google Scholar 

  37. Gorin NC, Najman A, van der Akker J, Aglietta M, Duhamel G (1982) Disappearance of Philadelphia chromosome after autologous bone marrow transplantation for treatment of chronic myeloid leukaemia in acute crisis. Lancet 1:44

    Google Scholar 

  38. Goto T, Nishikori M, Arlin Z et al (1982) Growth characteristics of leukemic and normal hematopoietic cells in Ph′ + chronic myelogenous leukemia and effects of intensive treatment. Blood 59:793–808

    PubMed  Google Scholar 

  39. Hayata I, Sakurai M, Kakati S, Sandberg A (1975) Chromosomes and causation of human cancer and leukemia. XVI. Banding studies of chronic myelocytic leukemia, including five unusual Ph′ translocations. Cancer 36:1177–1191

    PubMed  Google Scholar 

  40. Hogge DE, Coulombel L, Kalousek DK, Eaves CJ, Eaves AC (1987) Nonclonal hemopoietic progenitors in a G-6PD heterozygote with chronic myelogenous leukemia revealed after long-term marrow culture. Am J Hematol 24:389–394

    PubMed  Google Scholar 

  41. Hoyle C, Gray R, Goldman J (1994) Autografting for patients with CML in chronic phase: an update. Br J Haematol 86:76–81

    PubMed  Google Scholar 

  42. Jonas D, Lubbert M, Kawasaki ES, Henke M, Bross KJ, Mertelsman R, Herrmann F (1992) Clonal analyis of bcr-abl rearrangement in T lymphocytes from patients with chronic myeloid leukemia. Blood 79:1017–1023

    PubMed  Google Scholar 

  43. Kantarjian HM, Vellekoop L, Mc Credie KB et al (1985) Intensive combination chemotherapy (ROAP 10) and splenectomy in the management of chronic myelogenous leukemia. J Clin Oncol 3:192–200

    PubMed  Google Scholar 

  44. Kantarjian HM, Talpaz M, Le Maistre ChF et al (1991) Intensive combination chemotherapy and autologous transplantation leas to the reappearance of Philadelphia chromosomenegative cells in chronic myelogenous leukemia. Cancer 67:2959–2965

    PubMed  Google Scholar 

  45. Kantarjian H, Smith T, O'Brien S et al (1993) Prognostic factors for response and survical with alpha-interferon (IFN-A) therapy in early chronic-phase chronic myelogenous leukemia (CML). Blood 82 [Suppl 1]:378a

    Google Scholar 

  46. Körbling M, Burke Ph, Braine H, Elfenbein G, Santos G, Kaizer H (1981) Successful engraftment of blood derived normal hemopoietic stem cells in chronic myelogenous leukemia. Exp Hematol 6:684–690

    Google Scholar 

  47. Leemhuis T, Leibowitz D, Cox G, Srour EF, Tricot G, Hoffman R (1992) Selection of bcr/abl-negative progenitor cells from chronic myeloid leukemia marrow. In: Worthington-White DA, Gee AP, Gross S (eds) Advances in bone marrow purging and processing. Wiley-Liss Inc, New York, pp 231–237

    Google Scholar 

  48. Leemhuis T, Leibowitz D, Cox G, Siver R, Srour EF, Tricot G, Hoffman R (1993) Identification of BCR/ABL-negative primitive hematopoietic progenitor cells within chronic myeloid leukemia marrow. Blood 81:801–807

    PubMed  Google Scholar 

  49. Lisker R, Casas L, Mutchinick O, Pérez-Chávez F, Labardini J (1980) Late-appearing Philadelphia chromosome in two patients with chronic myelogenous leukemia. Blood 56:812–814

    PubMed  Google Scholar 

  50. Martin PJ, Najfeld V, Hansen JA, Penfold GJ, Jacobson RJ, Fialkow PJ (1980) Involvement of the B-lymphoid system in chronic myelogenous leukemia. Nature 298:49–50

    Google Scholar 

  51. Mc Glave Ph, Mamus S, Villen B, Dewald G (1987) Effect of recombinant gamma interferon on chronic myelogenous leukemia bone marrow progenitors. Exp Hematol 15:331–335

    PubMed  Google Scholar 

  52. Mc Glave PB, Arthur D, Miller WJ, Lasky L, Kersey J (1990) Autologous transplantation for CML using marrow treated ex vivo with recombinant human interferon gamma. Bone Marrow Transplant 6:115–120

    PubMed  Google Scholar 

  53. Mc Glave P, Bartsch G, Anasetti C, Ash R, Beatty P, Gasejewski J, Kernan NA (1993) Unrelated donor marrow transplantation therapy for chronic myelogenous leukemia: initial experience of the National Marrow Donor Program. Blood 81:543–550

    PubMed  Google Scholar 

  54. Mc Glave PB, De Fabriitis P, Goldman J et al (1994) Autologous transplant therapy for chronic myelogenous leukaemia prolongs survival: results from eight transplant groups. Lancet 343:1486–1488

    PubMed  Google Scholar 

  55. Miller JS, Verfaillie CM, Mc Glave PB (1990) Adherent lymphokine-activated killer (A-LAK) cells preferentially suppress chronic myelogenous leukemia (CML) primitive progenitors. Blood 76 [Suppl 1]: 1195

    Google Scholar 

  56. Mortensen BT, Ernst P, Philip P (1988) Mafosfamide (AstaZ-7654) in vitro treatment of bone marrow does not eradicate Philadelphia-positive cells in chronic myeloid leukemia. Eur J Hematol 41:218–222

    Google Scholar 

  57. Pasternak G, Pasternak L (1994) Persistence of bcr-abl mRNA-expressing cells in long-term cultures established from chronic myeloid leukemic bone marrow or blood. Ann Hematol 68:9–14

    PubMed  Google Scholar 

  58. Reiffers J, Trouette R, Marit G et al (1991) Autologous blood stem cell transplantation for chronic granulocytic leukaemia. Br J Haematol 77:339–345

    PubMed  Google Scholar 

  59. Sharp JC, Joyner MW, Wayne AW et al (1979) Karyotypic conversion in Ph′-positive chronic myeloid leukaemia with combination chemotherapy. Lancet 1:1370–1372

    PubMed  Google Scholar 

  60. Simonsson E, Oberg G, Bjiöreman M et al (1992) Intensive treatment in order to minimize the Ph-positive clone in chronic mycelogenous leukemia. Leuk Lymph 7 (suppl): 55–57

    Google Scholar 

  61. Singer JW, Arlin ZA, Najfeld V, Adamson JW, Kempin SJ, Clarkson BD, Fialkow PJ (1980) Restoration of nonclonal hematopoiesis in chronic myelogenous leukemia (CML) following a chemotherapy-induced loss of the Ph′ chromosome. Blood 56:356–360

    PubMed  Google Scholar 

  62. Smalley RV, Vogel J, Huguley CM jr, Miller D (1977) Chronic granulocytic leukemia: cytogenetic conversion of the bone marrow with cycle-specific therapy. Blood 50:107–113

    PubMed  Google Scholar 

  63. Sokal JE (1980) Significance of Ph′-negative marrow cells in Ph′-positive chronic granulocytic leukemia. Blood 56:1072–1076

    PubMed  Google Scholar 

  64. Sutherland HJ, Eaves CJ, Eaves AC, Dragowska W, Landsdorp PM (1989) Characterization and partial purification of human marrow cells capable of initating long-term hematopoiesis in vitro. Blood 74:1563–1570

    PubMed  Google Scholar 

  65. Strife A, Lambeck C, Wisniewski D, Wachter M, Gulati SC, Clarkson BD (1988) Discordant maturation as the primary biological defect in chronic myelogenous leukemia. Cancer Res 48:1035–1041

    PubMed  Google Scholar 

  66. Szcylik C, Skorski T, Nicolaides C et al (1991) Selective inhibition of leukemia cell proliferation by BCR-ABL antisense oligodeoxynucleotides. Science 253:562–565

    PubMed  Google Scholar 

  67. Talpaz M, Kantarjian HM, Kurzrock R, Trujillo JM, Gutterman JU (1991) Interferon-alpha produces sustained cytogenetic responses in chronic myelogenous leukemia Philadelphia chromosome-positive patients. Ann Intern Med 114:532–538

    PubMed  Google Scholar 

  68. Tura S (1993) Treatment of Ph-positive chronic myeloid leukemia with alph interferon (Roferon-A). The Italian Cooperative Study Group experience. Proceedings of the 2nd International Conference on CML, Bologna 1992. Leuk Lymph [Suppl 1]:153–157

    Google Scholar 

  69. Turhan AG, Humphries RK, Eaves CJ et al (1990) Detection of breakpoint cluster region-negative and nonclonal hematopoiesis in vitro and in vivo after transplantation of cells selected in cultures of chronic myeloid leukemia marrow. Blood 76:2404–2410

    PubMed  Google Scholar 

  70. Udomsakdi C, Eaves CJ, Landsdorp PM, Eaves AC (1992) Phenotypic heterogeneity of primitive leukemic hematopoietic cells in patients with chronic myeloid leukemia. Blood 80:2522–2530

    PubMed  Google Scholar 

  71. Verfaillie C, Miller W, Kay N, Mc Glave P (1989) Adherent lymphokineactivated killer cells in chronic myelogenous leukemia: a benign cell population with potent cytotoxic activity. Blood 74:793–797

    PubMed  Google Scholar 

  72. Verfaillie C, Blakholmer K, Mc Glave P (1990) Purified primitive human hematopoietic progenitors with long-term in vitro repopulating capacity adhere selectively to irradiated bone marrow stroma. J Exp Hematol 172:509–520

    Google Scholar 

  73. Verfallie CM, Mc Carthy JB, Mc Glave PhB (1992) Mechanisms underlying abnormal trafficking of malignant progenitors in chronic myelogenous leukemia. Decreased adhesion to stroma and fibronectin but increased adhesion to the basement membrane components laminin an collagen type IV. J Clin Invest 90:1232–1241

    PubMed  Google Scholar 

  74. Verfaillie CM, Miller WJ, Boylan K, Mc Glave PhB (1992) Selection of benign primitive hematopoietic progenitors in chronic myelogenous leukemia on the basis of HLA-DR antigen expression. Blood 79:1003–1010

    PubMed  Google Scholar 

  75. Vogler WR, Winton EF, James S, O'Neill S, Granade G, Mallard G (1983) Autologous transplantation after karyotypic conversion to normal in blastic phase of chronic myelocytic leukemia. Am J Med 75:1080–1084

    PubMed  Google Scholar 

  76. Von Denderen J, Hermans A, Meeuwswn T et al (1989) Antibody recognition of the tumor-specific bcr-abl joining region in chronic myeloid leukemia. J Exp Med 169:87–98

    PubMed  Google Scholar 

  77. Wognum AW, Krystal G, Eaves CJ, Eaves AC, Lansdorp PM (1992) Increased erythropoietin-receptor expression in CD34-positive bone marrow cells from patients with chronic myeloid leukemia. Blood 79:642–649

    PubMed  Google Scholar 

  78. Yuan T, Zhou YQ, Herst V et al (1992) Molecular approaches to purging of chronic myelogenous leukemia marrow in autologous transplantation. In: Worthington-White DA, Gee AP, Gross A (eds) Advances in bone marrow purging and processing. Wiley-Liss Inc, New York, pp 227–230

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Postgraduate School of Hematology “Farreras Valentí”, Servicio de Hematología, Hospital Clínic, Villarroel 170, E-08036, Barcelona, Spain

    F. Cervantes & C. Rozman

Authors
  1. F. Cervantes
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C. Rozman
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cervantes, F., Rozman, C. Benign hematopoietic progenitors in chronic myeloid leukemia: Current status and future prospects. Ann Hematol 69, 99–105 (1994). https://doi.org/10.1007/BF01695688

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01695688

Key words

Search

Navigation