Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1998 Aug 15;102(4):710–715. doi: 10.1172/JCI3094

Treatment with interferon-alpha preferentially reduces the capacity for amplification of granulocyte-macrophage progenitors (CFU-GM) from patients with chronic myeloid leukemia but spares normal CFU-GM.

M Y Gordon 1, S B Marley 1, J L Lewis 1, R J Davidson 1, D X Nguyen 1, F H Grand 1, T A Amos 1, J M Goldman 1
PMCID: PMC508933  PMID: 9710439

Abstract

The biological target for interferon (IFN)-alpha in chronic myeloid leukemia (CML) is unknown, but one possibility is that amplification of granulocyte-macrophage colony-forming cells (CFU-GM) is reduced. Replating CFU-GM colonies and observing secondary colony formation provides a measure of CFU-GM amplification. Amplification of CML, but not normal, CFU-GM in vitro was significantly inhibited by IFN-alpha (P = 0.02). In 5 out of 15 CML cases studied by fluorescence in situ hybridization, in vitro treatment with IFN-alpha increased the proportion of CFU-GM, which lacked BCR-ABL. The ability of patients' CFU-GM to amplify, and suppression of this ability by IFN-alpha, predicted responsiveness to IFN-alpha therapy in 86% of cases. Investigation of patients on treatment with IFN-alpha showed a threefold reduction in CFU-GM amplification in responders (P = 0.03) but no significant change in nonresponders (P = 0.8). We conclude that IFN-alpha preferentially suppresses amplification of CML CFU-GM to varying degrees. The differing in vitro sensitivities to IFN-alpha and growth kinetics of individual patients' cells could help differentiate those who will or will not benefit from treatment with IFN-alpha.

Full Text

The Full Text of this article is available as a PDF (160.9 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Albrecht T., Schwab R., Henkes M., Peschel C., Huber C., Aulitzky W. E. Primary proliferating immature myeloid cells from CML patients are not resistant to induction of apoptosis by DNA damage and growth factor withdrawal. Br J Haematol. 1996 Dec;95(3):501–507. doi: 10.1046/j.1365-2141.1996.d01-1934.x. [DOI] [PubMed] [Google Scholar]
  2. Amos T. A., Lewis J. L., Grand F. H., Gooding R. P., Goldman J. M., Gordon M. Y. Apoptosis in chronic myeloid leukaemia: normal responses by progenitor cells to growth factor deprivation, X-irradiation and glucocorticoids. Br J Haematol. 1995 Oct;91(2):387–393. doi: 10.1111/j.1365-2141.1995.tb05308.x. [DOI] [PubMed] [Google Scholar]
  3. Bedi A., Zehnbauer B. A., Barber J. P., Sharkis S. J., Jones R. J. Inhibition of apoptosis by BCR-ABL in chronic myeloid leukemia. Blood. 1994 Apr 15;83(8):2038–2044. [PubMed] [Google Scholar]
  4. Bernier J., Reuter A., Vrindts-Gevaert Y., Franchimont P. Radioimmunoassay of leukocyte (alpha) interferon and its application to some clinical conditions. J Nucl Med. 1984 Jul;25(7):765–772. [PubMed] [Google Scholar]
  5. Bhatia R., Wayner E. A., McGlave P. B., Verfaillie C. M. Interferon-alpha restores normal adhesion of chronic myelogenous leukemia hematopoietic progenitors to bone marrow stroma by correcting impaired beta 1 integrin receptor function. J Clin Invest. 1994 Jul;94(1):384–391. doi: 10.1172/JCI117333. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Carlo-Stella C., Dotti G., Mangoni L., Regazzi E., Garau D., Bonati A., Almici C., Sammarelli G., Savoldo B., Rizzo M. T. Selection of myeloid progenitors lacking BCR/ABL mRNA in chronic myelogenous leukemia patients after in vitro treatment with the tyrosine kinase inhibitor genistein. Blood. 1996 Oct 15;88(8):3091–3100. [PubMed] [Google Scholar]
  7. Corssmit E. P., Heijligenberg R., Hack C. E., Endert E., Sauerwein H. P., Romijn J. A. Effects of interferon-alpha (IFN-alpha) administration on leucocytes in healthy humans. Clin Exp Immunol. 1997 Feb;107(2):359–363. doi: 10.1111/j.1365-2249.1997.269-ce1161.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Dowding C., Guo A. P., Maisin D., Gordon M. Y., Goldman J. M. The effects of interferon-alpha on the proliferation of CML progenitor cells in vitro are not related to the precise position of the M-BCR breakpoint. Br J Haematol. 1991 Feb;77(2):165–171. doi: 10.1111/j.1365-2141.1991.tb07972.x. [DOI] [PubMed] [Google Scholar]
  9. Dowding C., Guo A. P., Osterholz J., Siczkowski M., Goldman J., Gordon M. Interferon-alpha overrides the deficient adhesion of chronic myeloid leukemia primitive progenitor cells to bone marrow stromal cells. Blood. 1991 Jul 15;78(2):499–505. [PubMed] [Google Scholar]
  10. Eaves C. J., Eaves A. C. Stem cell kinetics. Baillieres Clin Haematol. 1997 Jun;10(2):233–257. doi: 10.1016/s0950-3536(97)80005-4. [DOI] [PubMed] [Google Scholar]
  11. Galvani D. W., Cawley J. C. Mechanism of action of alpha interferon in chronic granulocytic leukaemia: evidence for preferential inhibition of late progenitors. Br J Haematol. 1989 Dec;73(4):475–479. doi: 10.1111/j.1365-2141.1989.tb00283.x. [DOI] [PubMed] [Google Scholar]
  12. Gordon M. Y., Atkinson J., Clarke D., Dowding C. R., Goldman J. M., Grimsley P. G., Siczkowski M., Greaves M. F. Deficiency of a phosphatidylinositol-anchored cell adhesion molecule influences haemopoietic progenitor binding to marrow stroma in chronic myeloid leukaemia. Leukemia. 1991 Aug;5(8):693–698. [PubMed] [Google Scholar]
  13. Gordon M. Y., Dowding C. R., Riley G. P., Goldman J. M., Greaves M. F. Altered adhesive interactions with marrow stroma of haematopoietic progenitor cells in chronic myeloid leukaemia. Nature. 1987 Jul 23;328(6128):342–344. doi: 10.1038/328342a0. [DOI] [PubMed] [Google Scholar]
  14. Gordon M. Y., Goldman J. M. Cellular and molecular mechanisms in chronic myeloid leukaemia: biology and treatment. Br J Haematol. 1996 Oct;95(1):10–20. [PubMed] [Google Scholar]
  15. Gordon M. Y., Lewis J. L., Grand F. H., Marley S. B., Goldman J. M. Phenotype and progeny of primitive adherent human hematopoietic progenitors. Leukemia. 1996 Aug;10(8):1347–1353. [PubMed] [Google Scholar]
  16. Gordon M. Y., Lewis J. L., Marley S. B., Grand F. H., Goldman J. M. Stromal cells negatively regulate primitive haemopoietic progenitor cell activation via a phosphatidylinositol-anchored cell adhesion/signalling mechanism. Br J Haematol. 1997 Mar;96(3):647–653. [PubMed] [Google Scholar]
  17. Gordon M. Y. Plastic-adherent cells in human bone marrow generate long-term hematopoiesis in vitro. Leukemia. 1994 May;8(5):865–870. [PubMed] [Google Scholar]
  18. Grand F. H., Marley S. B., Chase A., Titley I., Healy L., Spencer A., Reiter A., Goldman J. M., Gordon M. Y. BCR/ABL-negative progenitors are enriched in the adherent fraction of CD34+ cells circulating in the blood of chronic phase chronic myeloid leukemia patients. Leukemia. 1997 Sep;11(9):1486–1492. doi: 10.1038/sj.leu.2400748. [DOI] [PubMed] [Google Scholar]
  19. Grunfeld C., Kotler D. P., Shigenaga J. K., Doerrler W., Tierney A., Wang J., Pierson R. N., Jr, Feingold K. R. Circulating interferon-alpha levels and hypertriglyceridemia in the acquired immunodeficiency syndrome. Am J Med. 1991 Feb;90(2):154–162. [PubMed] [Google Scholar]
  20. Marley S. B., Lewis J. L., Scott M. A., Goldman J. M., Gordon M. Y. Evaluation of "discordant maturation' in chronic myeloid leukaemia using cultures of primitive progenitor cells and their production of clonogenic progeny (CFU-GM). Br J Haematol. 1996 Nov;95(2):299–305. doi: 10.1046/j.1365-2141.1996.d01-1910.x. [DOI] [PubMed] [Google Scholar]
  21. Roger R., Issaad C., Pallardy M., Léglise M. C., Turhan A. G., Bertoglio J., Bréard J. BCR-ABL does not prevent apoptotic death induced by human natural killer or lymphokine-activated killer cells. Blood. 1996 Feb 1;87(3):1113–1122. [PubMed] [Google Scholar]
  22. Selleri C., Sato T., Del Vecchio L., Luciano L., Barrett A. J., Rotoli B., Young N. S., Maciejewski J. P. Involvement of Fas-mediated apoptosis in the inhibitory effects of interferon-alpha in chronic myelogenous leukemia. Blood. 1997 Feb 1;89(3):957–964. [PubMed] [Google Scholar]
  23. Sherwin S. A., Knost J. A., Fein S., Abrams P. G., Foon K. A., Ochs J. J., Schoenberger C., Maluish A. E., Oldham R. K. A multiple-dose phase I trial of recombinant leukocyte A interferon in cancer patients. JAMA. 1982 Nov 19;248(19):2461–2466. [PubMed] [Google Scholar]
  24. Talpaz M., Kantarjian H. M., McCredie K., Trujillo J. M., Keating M. J., Gutterman J. U. Hematologic remission and cytogenetic improvement induced by recombinant human interferon alpha A in chronic myelogenous leukemia. N Engl J Med. 1986 Apr 24;314(17):1065–1069. doi: 10.1056/NEJM198604243141701. [DOI] [PubMed] [Google Scholar]
  25. Talpaz M., McCredie K., Kantarjian H., Trujillo J., Keating M., Gutterman J. Chronic myelogenous leukaemia: haematological remissions with alpha interferon. Br J Haematol. 1986 Sep;64(1):87–95. doi: 10.1111/j.1365-2141.1986.tb07576.x. [DOI] [PubMed] [Google Scholar]
  26. Udomsakdi C., Eaves C. J., Swolin B., Reid D. S., Barnett M. J., Eaves A. C. Rapid decline of chronic myeloid leukemic cells in long-term culture due to a defect at the leukemic stem cell level. Proc Natl Acad Sci U S A. 1992 Jul 1;89(13):6192–6196. doi: 10.1073/pnas.89.13.6192. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Verfaillie C. M., McCarthy J. B., McGlave P. B. 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 and collagen type IV. J Clin Invest. 1992 Oct;90(4):1232–1241. doi: 10.1172/JCI115985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Williams C. K., Svet-Moldavskaya I., Vilcek J., Ohnuma T., Holland J. F. Inhibitory effects of human leukocyte and fibroblast interferons on normal and chronic myelogenous leukemic granulocytic progenitor cells. Oncology. 1981;38(6):356–360. doi: 10.1159/000225587. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES