Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1992 Oct;90(4):1232–1241. doi: 10.1172/JCI115985

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.

C M Verfaillie 1, J B McCarthy 1, P B McGlave 1
PMCID: PMC443164  PMID: 1383271

Abstract

We studied the adhesion of primitive and committed progenitors from chronic myelogenous leukemia (CML) and normal bone marrow to stroma and to several extracellular matrix components. In contrast to benign primitive progenitors from CML or normal bone marrow, Ph1-positive primitive progenitors from CML bone marrow fail to adhere to normal stromal layers and to fibronectin and its proteolytic fragments, but do adhere to collagen type IV, an extracellular matrix component of basement membranes. Similarly, multilineage colony-forming unit (CFU-MIX) progenitors from CML bone marrow do not adhere to fibronectin or its adhesion promoting fragments but adhere to collagen type IV. Unlike committed progenitors from normal bone marrow, CML single-lineage burst-forming units-erythroid and granulocyte/macrophage colony-forming units fail to adhere to fibronectin or its components but do adhere to both collagen type IV and laminin. Evaluation of adhesion receptor expression demonstrates that fibronectin receptors (alpha 4, alpha 5, and beta 1) are equally present on progenitors from normal and CML bone marrow. However, a fraction of CML progenitors express alpha 2 and alpha 6 receptors, associated with laminin and collagens, whereas these receptors are absent from normal progenitors. These observations indicate that the premature release of malignant Ph1-positive progenitors into the circulation may be caused by loss of adhesive interactions with stroma and/or fibronectin and acquisition of adhesive interactions with basement membrane components. Further study of the altered function of cell-surface adhesion receptors characteristic of the malignant clone in CML may lead to a better understanding of the mechanisms underlying both abnormal expansion and abnormal circulation of malignant progenitors in CML.

Full text

PDF

Selected References

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

  1. Andrews R. G., Singer J. W., Bernstein I. D. Human hematopoietic precursors in long-term culture: single CD34+ cells that lack detectable T cell, B cell, and myeloid cell antigens produce multiple colony-forming cells when cultured with marrow stromal cells. J Exp Med. 1990 Jul 1;172(1):355–358. doi: 10.1084/jem.172.1.355. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Campbell A. D., Long M. W., Wicha M. S. Haemonectin, a bone marrow adhesion protein specific for cells of granulocyte lineage. Nature. 1987 Oct 22;329(6141):744–746. doi: 10.1038/329744a0. [DOI] [PubMed] [Google Scholar]
  3. Chelberg M. K., Tsilibary E. C., Hauser A. R., McCarthy J. B. Type IV collagen-mediated melanoma cell adhesion and migration: involvement of multiple, distinct domains of the collagen molecule. Cancer Res. 1989 Sep 1;49(17):4796–4802. [PubMed] [Google Scholar]
  4. Coulombel L., Eaves A. C., Eaves C. J. Enzymatic treatment of long-term human marrow cultures reveals the preferential location of primitive hemopoietic progenitors in the adherent layer. Blood. 1983 Aug;62(2):291–297. [PubMed] [Google Scholar]
  5. Dedhar S., Saulnier R. Alterations in integrin receptor expression on chemically transformed human cells: specific enhancement of laminin and collagen receptor complexes. J Cell Biol. 1990 Feb;110(2):481–489. doi: 10.1083/jcb.110.2.481. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Dexter T. M., Moore M. A., Sheridan A. P. Maintenance of hemopoietic stem cells and production of differentiated progeny in allogeneic and semiallogeneic bone marrow chimeras in vitro. J Exp Med. 1977 Jun 1;145(6):1612–1616. doi: 10.1084/jem.145.6.1612. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. 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]
  8. Eaves C. J., Cashman J. D., Kay R. J., Dougherty G. J., Otsuka T., Gaboury L. A., Hogge D. E., Lansdorp P. M., Eaves A. C., Humphries R. K. Mechanisms that regulate the cell cycle status of very primitive hematopoietic cells in long-term human marrow cultures. II. Analysis of positive and negative regulators produced by stromal cells within the adherent layer. Blood. 1991 Jul 1;78(1):110–117. [PubMed] [Google Scholar]
  9. 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]
  10. Harlan J. M. Leukocyte-endothelial interactions. Blood. 1985 Mar;65(3):513–525. [PubMed] [Google Scholar]
  11. Hemler M. E., Huang C., Schwarz L. The VLA protein family. Characterization of five distinct cell surface heterodimers each with a common 130,000 molecular weight beta subunit. J Biol Chem. 1987 Mar 5;262(7):3300–3309. [PubMed] [Google Scholar]
  12. Kantarjian H. M., Smith T. L., McCredie K. B., Keating M. J., Walters R. S., Talpaz M., Hester J. P., Bligham G., Gehan E., Freireich E. J. Chronic myelogenous leukemia: a multivariate analysis of the associations of patient characteristics and therapy with survival. Blood. 1985 Dec;66(6):1326–1335. [PubMed] [Google Scholar]
  13. Kennedy D. W., Rohrbach D. H., Martin G. R., Momoi T., Yamada K. M. The adhesive glycoprotein laminin is an agglutinin. J Cell Physiol. 1983 Mar;114(3):257–262. doi: 10.1002/jcp.1041140302. [DOI] [PubMed] [Google Scholar]
  14. Kramer R. H., Bensch K. G., Wong J. Invasion of reconstituted basement membrane matrix by metastatic human tumor cells. Cancer Res. 1986 Apr;46(4 Pt 2):1980–1989. [PubMed] [Google Scholar]
  15. Liotta L. A., Kleinerman J., Catanzaro P., Rynbrandt D. Degradation of basement membrane by murine tumor cells. J Natl Cancer Inst. 1977 May;58(5):1427–1431. doi: 10.1093/jnci/58.5.1427. [DOI] [PubMed] [Google Scholar]
  16. Long M. W., Dixit V. M. Thrombospondin functions as a cytoadhesion molecule for human hematopoietic progenitor cells. Blood. 1990 Jun 15;75(12):2311–2318. [PubMed] [Google Scholar]
  17. Martin G. R., Timpl R. Laminin and other basement membrane components. Annu Rev Cell Biol. 1987;3:57–85. doi: 10.1146/annurev.cb.03.110187.000421. [DOI] [PubMed] [Google Scholar]
  18. McCarthy J. B., Hagen S. T., Furcht L. T. Human fibronectin contains distinct adhesion- and motility-promoting domains for metastatic melanoma cells. J Cell Biol. 1986 Jan;102(1):179–188. doi: 10.1083/jcb.102.1.179. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Patel V. P., Lodish H. F. A fibronectin matrix is required for differentiation of murine erythroleukemia cells into reticulocytes. J Cell Biol. 1987 Dec;105(6 Pt 2):3105–3118. doi: 10.1083/jcb.105.6.3105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Plantefaber L. C., Hynes R. O. Changes in integrin receptors on oncogenically transformed cells. Cell. 1989 Jan 27;56(2):281–290. doi: 10.1016/0092-8674(89)90902-1. [DOI] [PubMed] [Google Scholar]
  21. Rohrschneider L. R., Najita L. M. Detection of the v-abl gene product at cell-substratum contact sites in Abelson murine leukemia virus-transformed fibroblasts. J Virol. 1984 Aug;51(2):547–552. doi: 10.1128/jvi.51.2.547-552.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Shaw L. M., Messier J. M., Mercurio A. M. The activation dependent adhesion of macrophages to laminin involves cytoskeletal anchoring and phosphorylation of the alpha 6 beta 1 integrin. J Cell Biol. 1990 Jun;110(6):2167–2174. doi: 10.1083/jcb.110.6.2167. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Simmons P. J., Torok-Storb B. Identification of stromal cell precursors in human bone marrow by a novel monoclonal antibody, STRO-1. Blood. 1991 Jul 1;78(1):55–62. [PubMed] [Google Scholar]
  24. Sonnenberg A., Modderman P. W., Hogervorst F. Laminin receptor on platelets is the integrin VLA-6. Nature. 1988 Dec 1;336(6198):487–489. doi: 10.1038/336487a0. [DOI] [PubMed] [Google Scholar]
  25. Sutherland H. J., Eaves C. J., Eaves A. C., Dragowska W., Lansdorp P. M. Characterization and partial purification of human marrow cells capable of initiating long-term hematopoiesis in vitro. Blood. 1989 Oct;74(5):1563–1570. [PubMed] [Google Scholar]
  26. 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]
  27. Timpl R. Structure and biological activity of basement membrane proteins. Eur J Biochem. 1989 Apr 1;180(3):487–502. doi: 10.1111/j.1432-1033.1989.tb14673.x. [DOI] [PubMed] [Google Scholar]
  28. Turhan A. G., Humphries R. K., Eaves C. J., Barnett M. J., Phillips G. L., Kalousek D. K., Klingemann H. G., Lansdorp P. L., Reece D. E., Shepherd J. D. 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. 1990 Dec 1;76(11):2404–2410. [PubMed] [Google Scholar]
  29. Van Etten R. A., Jackson P., Baltimore D. The mouse type IV c-abl gene product is a nuclear protein, and activation of transforming ability is associated with cytoplasmic localization. Cell. 1989 Aug 25;58(4):669–678. doi: 10.1016/0092-8674(89)90102-5. [DOI] [PubMed] [Google Scholar]
  30. Verfaillie C. M., McCarthy J. B., McGlave P. B. Differentiation of primitive human multipotent hematopoietic progenitors into single lineage clonogenic progenitors is accompanied by alterations in their interaction with fibronectin. J Exp Med. 1991 Sep 1;174(3):693–703. doi: 10.1084/jem.174.3.693. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Verfaillie C. M., Miller W. J., Boylan K., McGlave P. B. Selection of benign primitive hematopoietic progenitors in chronic myelogenous leukemia on the basis of HLA-DR antigen expression. Blood. 1992 Feb 15;79(4):1003–1010. [PubMed] [Google Scholar]
  32. Verfaillie C., Blakolmer K., McGlave P. Purified primitive human hematopoietic progenitor cells with long-term in vitro repopulating capacity adhere selectively to irradiated bone marrow stroma. J Exp Med. 1990 Aug 1;172(2):509–502. doi: 10.1084/jem.172.2.509. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Vuillet-Gaugler M. H., Breton-Gorius J., Vainchenker W., Guichard J., Leroy C., Tchernia G., Coulombel L. Loss of attachment to fibronectin with terminal human erythroid differentiation. Blood. 1990 Feb 15;75(4):865–873. [PubMed] [Google Scholar]
  34. Zuckerman K. S., Wicha M. S. Extracellular matrix production by the adherent cells of long-term murine bone marrow cultures. Blood. 1983 Mar;61(3):540–547. [PubMed] [Google Scholar]
  35. de Klein A., van Kessel A. G., Grosveld G., Bartram C. R., Hagemeijer A., Bootsma D., Spurr N. K., Heisterkamp N., Groffen J., Stephenson J. R. A cellular oncogene is translocated to the Philadelphia chromosome in chronic myelocytic leukaemia. Nature. 1982 Dec 23;300(5894):765–767. doi: 10.1038/300765a0. [DOI] [PubMed] [Google Scholar]

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

RESOURCES