Skip to main content
PMC home page
Molecular and Cellular Biology logoLink to Molecular and Cellular Biology
. 1995 Mar;15(3):1286–1293. doi: 10.1128/mcb.15.3.1286

The human leukemia oncogene bcr-abl abrogates the anchorage requirement but not the growth factor requirement for proliferation.

M W Renshaw 1, J R McWhirter 1, J Y Wang 1
PMCID: PMC230351  PMID: 7862122

Abstract

Proliferation of normal cells in a multicellular organism requires not only growth factors but also the proper attachment to the extracellular matrix. A hallmark of neoplastic transformation is the loss of anchorage dependence which usually accompanies the loss of growth factor requirement. The Bcr-Abl tyrosine kinase of human leukemias is shown here to abrogate only the anchorage, not the growth factor, requirement. Bcr-Abl-transformed cells grow in soft agar but do not proliferate in serum-free media. Bcr-Abl does not activate the mitogenic pathway, as indicated by its inability to induce enhancers such as the serum response element or the tetradecanoyl phorbol acetate response element (TRE). However, Bcr-Abl can alleviate the anchorage requirement for the induction of the TRE enhancer; i.e., it allows serum to activate the TRE in detached cells. This activity is dependent on the association of an active Bcr-Abl tyrosine kinase with the actin filaments. Despite its association with the adapter protein Grb2, Bcr-Abl's effect on the TRE enhancer is not blocked by dominant negative Ras or Raf. The finding that Bcr-Abl tyrosine kinase abrogates only anchorage dependence may have important implications on the pathogenesis of chronic myelogenous leukemia.

Full Text

The Full Text of this article is available as a PDF (268.5 KB).

Selected References

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

  1. Angel P., Hattori K., Smeal T., Karin M. The jun proto-oncogene is positively autoregulated by its product, Jun/AP-1. Cell. 1988 Dec 2;55(5):875–885. doi: 10.1016/0092-8674(88)90143-2. [DOI] [PubMed] [Google Scholar]
  2. Aronheim A., Engelberg D., Li N., al-Alawi N., Schlessinger J., Karin M. Membrane targeting of the nucleotide exchange factor Sos is sufficient for activating the Ras signaling pathway. Cell. 1994 Sep 23;78(6):949–961. doi: 10.1016/0092-8674(94)90271-2. [DOI] [PubMed] [Google Scholar]
  3. Burridge K., Petch L. A., Romer L. H. Signals from focal adhesions. Curr Biol. 1992 Oct;2(10):537–539. doi: 10.1016/0960-9822(92)90020-b. [DOI] [PubMed] [Google Scholar]
  4. Campisi J., Medrano E. E. Cell cycle perturbations in normal and transformed fibroblasts caused by detachment from the substratum. J Cell Physiol. 1983 Jan;114(1):53–60. doi: 10.1002/jcp.1041140109. [DOI] [PubMed] [Google Scholar]
  5. Champlin R. E., Golde D. W. Chronic myelogenous leukemia: recent advances. Blood. 1985 May;65(5):1039–1047. [PubMed] [Google Scholar]
  6. Chan L. C., Karhi K. K., Rayter S. I., Heisterkamp N., Eridani S., Powles R., Lawler S. D., Groffen J., Foulkes J. G., Greaves M. F. A novel abl protein expressed in Philadelphia chromosome positive acute lymphoblastic leukaemia. Nature. 1987 Feb 12;325(6105):635–637. doi: 10.1038/325635a0. [DOI] [PubMed] [Google Scholar]
  7. Daley G. Q., Baltimore D. Transformation of an interleukin 3-dependent hematopoietic cell line by the chronic myelogenous leukemia-specific P210bcr/abl protein. Proc Natl Acad Sci U S A. 1988 Dec;85(23):9312–9316. doi: 10.1073/pnas.85.23.9312. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Daley G. Q., Ben-Neriah Y. Implicating the bcr/abl gene in the pathogenesis of Philadelphia chromosome-positive human leukemia. Adv Cancer Res. 1991;57:151–184. doi: 10.1016/s0065-230x(08)60998-7. [DOI] [PubMed] [Google Scholar]
  9. Daley G. Q., McLaughlin J., Witte O. N., Baltimore D. The CML-specific P210 bcr/abl protein, unlike v-abl, does not transform NIH/3T3 fibroblasts. Science. 1987 Jul 31;237(4814):532–535. doi: 10.1126/science.2440107. [DOI] [PubMed] [Google Scholar]
  10. Daley G. Q., Van Etten R. A., Baltimore D. Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. Science. 1990 Feb 16;247(4944):824–830. doi: 10.1126/science.2406902. [DOI] [PubMed] [Google Scholar]
  11. Daley G. Q., Van Etten R. A., Jackson P. K., Bernards A., Baltimore D. Nonmyristoylated Abl proteins transform a factor-dependent hematopoietic cell line. Mol Cell Biol. 1992 Apr;12(4):1864–1871. doi: 10.1128/mcb.12.4.1864. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Deschamps J., Meijlink F., Verma I. M. Identification of a transcriptional enhancer element upstream from the proto-oncogene fos. Science. 1985 Dec 6;230(4730):1174–1177. doi: 10.1126/science.3865371. [DOI] [PubMed] [Google Scholar]
  13. 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]
  14. Eaves A. C., Cashman J. D., Gaboury L. A., Kalousek D. K., Eaves C. J. Unregulated proliferation of primitive chronic myeloid leukemia progenitors in the presence of normal marrow adherent cells. Proc Natl Acad Sci U S A. 1986 Jul;83(14):5306–5310. doi: 10.1073/pnas.83.14.5306. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Eaves A. C., Eaves C. J. Maintenance and proliferation control of primitive hemopoietic progenitors in long-term cultures of human marrow cells. Blood Cells. 1988;14(2-3):355–368. [PubMed] [Google Scholar]
  16. Fainstein E., Einat M., Gokkel E., Marcelle C., Croce C. M., Gale R. P., Canaani E. Nucleotide sequence analysis of human abl and bcr-abl cDNAs. Oncogene. 1989 Dec;4(12):1477–1481. [PubMed] [Google Scholar]
  17. Feinstein E., Cimino G., Gale R. P., Alimena G., Berthier R., Kishi K., Goldman J., Zaccaria A., Berrebi A., Canaani E. p53 in chronic myelogenous leukemia in acute phase. Proc Natl Acad Sci U S A. 1991 Jul 15;88(14):6293–6297. doi: 10.1073/pnas.88.14.6293. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Gishizky M. L., Witte O. N. Initiation of deregulated growth of multipotent progenitor cells by bcr-abl in vitro. Science. 1992 May 8;256(5058):836–839. doi: 10.1126/science.1375394. [DOI] [PubMed] [Google Scholar]
  19. Goff S. P., Tabin C. J., Wang J. Y., Weinberg R., Baltimore D. Transfection of fibroblasts by cloned Abelson murine leukemia virus DNA and recovery of transmissible virus by recombination with helper virus. J Virol. 1982 Jan;41(1):271–285. doi: 10.1128/jvi.41.1.271-285.1982. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. 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]
  21. Graham F. L., van der Eb A. J. A new technique for the assay of infectivity of human adenovirus 5 DNA. Virology. 1973 Apr;52(2):456–467. doi: 10.1016/0042-6822(73)90341-3. [DOI] [PubMed] [Google Scholar]
  22. Greenberg M. E., Ziff E. B. Stimulation of 3T3 cells induces transcription of the c-fos proto-oncogene. Nature. 1984 Oct 4;311(5985):433–438. doi: 10.1038/311433a0. [DOI] [PubMed] [Google Scholar]
  23. Gutterman J. U. Cytokine therapeutics: lessons from interferon alpha. Proc Natl Acad Sci U S A. 1994 Feb 15;91(4):1198–1205. doi: 10.1073/pnas.91.4.1198. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Halazonetis T. D., Georgopoulos K., Greenberg M. E., Leder P. c-Jun dimerizes with itself and with c-Fos, forming complexes of different DNA binding affinities. Cell. 1988 Dec 2;55(5):917–924. doi: 10.1016/0092-8674(88)90147-x. [DOI] [PubMed] [Google Scholar]
  25. Herbomel P., Bourachot B., Yaniv M. Two distinct enhancers with different cell specificities coexist in the regulatory region of polyoma. Cell. 1984 Dec;39(3 Pt 2):653–662. doi: 10.1016/0092-8674(84)90472-0. [DOI] [PubMed] [Google Scholar]
  26. Kelliher M. A., McLaughlin J., Witte O. N., Rosenberg N. Induction of a chronic myelogenous leukemia-like syndrome in mice with v-abl and BCR/ABL. Proc Natl Acad Sci U S A. 1990 Sep;87(17):6649–6653. doi: 10.1073/pnas.87.17.6649. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Kornberg L., Earp H. S., Parsons J. T., Schaller M., Juliano R. L. Cell adhesion or integrin clustering increases phosphorylation of a focal adhesion-associated tyrosine kinase. J Biol Chem. 1992 Nov 25;267(33):23439–23442. [PubMed] [Google Scholar]
  28. Kurzrock R., Shtalrid M., Romero P., Kloetzer W. S., Talpas M., Trujillo J. M., Blick M., Beran M., Gutterman J. U. A novel c-abl protein product in Philadelphia-positive acute lymphoblastic leukaemia. Nature. 1987 Feb 12;325(6105):631–635. doi: 10.1038/325631a0. [DOI] [PubMed] [Google Scholar]
  29. Leevers S. J., Paterson H. F., Marshall C. J. Requirement for Ras in Raf activation is overcome by targeting Raf to the plasma membrane. Nature. 1994 Jun 2;369(6479):411–414. doi: 10.1038/369411a0. [DOI] [PubMed] [Google Scholar]
  30. Lugo T. G., Pendergast A. M., Muller A. J., Witte O. N. Tyrosine kinase activity and transformation potency of bcr-abl oncogene products. Science. 1990 Mar 2;247(4946):1079–1082. doi: 10.1126/science.2408149. [DOI] [PubMed] [Google Scholar]
  31. Lugo T. G., Witte O. N. The BCR-ABL oncogene transforms Rat-1 cells and cooperates with v-myc. Mol Cell Biol. 1989 Mar;9(3):1263–1270. doi: 10.1128/mcb.9.3.1263. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Marais R., Wynne J., Treisman R. The SRF accessory protein Elk-1 contains a growth factor-regulated transcriptional activation domain. Cell. 1993 Apr 23;73(2):381–393. doi: 10.1016/0092-8674(93)90237-k. [DOI] [PubMed] [Google Scholar]
  33. McLaughlin J., Chianese E., Witte O. N. Alternative forms of the BCR-ABL oncogene have quantitatively different potencies for stimulation of immature lymphoid cells. Mol Cell Biol. 1989 May;9(5):1866–1874. doi: 10.1128/mcb.9.5.1866. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. McLaughlin J., Chianese E., Witte O. N. In vitro transformation of immature hematopoietic cells by the P210 BCR/ABL oncogene product of the Philadelphia chromosome. Proc Natl Acad Sci U S A. 1987 Sep;84(18):6558–6562. doi: 10.1073/pnas.84.18.6558. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. McWhirter J. R., Galasso D. L., Wang J. Y. A coiled-coil oligomerization domain of Bcr is essential for the transforming function of Bcr-Abl oncoproteins. Mol Cell Biol. 1993 Dec;13(12):7587–7595. doi: 10.1128/mcb.13.12.7587. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. McWhirter J. R., Wang J. Y. Activation of tyrosinase kinase and microfilament-binding functions of c-abl by bcr sequences in bcr/abl fusion proteins. Mol Cell Biol. 1991 Mar;11(3):1553–1565. doi: 10.1128/mcb.11.3.1553. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. McWhirter J. R., Wang J. Y. An actin-binding function contributes to transformation by the Bcr-Abl oncoprotein of Philadelphia chromosome-positive human leukemias. EMBO J. 1993 Apr;12(4):1533–1546. doi: 10.1002/j.1460-2075.1993.tb05797.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Morla A. O., Draetta G., Beach D., Wang J. Y. Reversible tyrosine phosphorylation of cdc2: dephosphorylation accompanies activation during entry into mitosis. Cell. 1989 Jul 14;58(1):193–203. doi: 10.1016/0092-8674(89)90415-7. [DOI] [PubMed] [Google Scholar]
  39. Nakabeppu Y., Ryder K., Nathans D. DNA binding activities of three murine Jun proteins: stimulation by Fos. Cell. 1988 Dec 2;55(5):907–915. doi: 10.1016/0092-8674(88)90146-8. [DOI] [PubMed] [Google Scholar]
  40. O'Neill C., Jordan P., Ireland G. Evidence for two distinct mechanisms of anchorage stimulation in freshly explanted and 3T3 Swiss mouse fibroblasts. Cell. 1986 Feb 14;44(3):489–496. doi: 10.1016/0092-8674(86)90470-8. [DOI] [PubMed] [Google Scholar]
  41. Olivier J. P., Raabe T., Henkemeyer M., Dickson B., Mbamalu G., Margolis B., Schlessinger J., Hafen E., Pawson T. A Drosophila SH2-SH3 adaptor protein implicated in coupling the sevenless tyrosine kinase to an activator of Ras guanine nucleotide exchange, Sos. Cell. 1993 Apr 9;73(1):179–191. doi: 10.1016/0092-8674(93)90170-u. [DOI] [PubMed] [Google Scholar]
  43. Pendergast A. M., Muller A. J., Havlik M. H., Maru Y., Witte O. N. BCR sequences essential for transformation by the BCR-ABL oncogene bind to the ABL SH2 regulatory domain in a non-phosphotyrosine-dependent manner. Cell. 1991 Jul 12;66(1):161–171. doi: 10.1016/0092-8674(91)90148-r. [DOI] [PubMed] [Google Scholar]
  44. Pendergast A. M., Quilliam L. A., Cripe L. D., Bassing C. H., Dai Z., Li N., Batzer A., Rabun K. M., Der C. J., Schlessinger J. BCR-ABL-induced oncogenesis is mediated by direct interaction with the SH2 domain of the GRB-2 adaptor protein. Cell. 1993 Oct 8;75(1):175–185. [PubMed] [Google Scholar]
  45. Puil L., Liu J., Gish G., Mbamalu G., Bowtell D., Pelicci P. G., Arlinghaus R., Pawson T. Bcr-Abl oncoproteins bind directly to activators of the Ras signalling pathway. EMBO J. 1994 Feb 15;13(4):764–773. doi: 10.1002/j.1460-2075.1994.tb06319.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Renshaw M. W., Kipreos E. T., Albrecht M. R., Wang J. Y. Oncogenic v-Abl tyrosine kinase can inhibit or stimulate growth, depending on the cell context. EMBO J. 1992 Nov;11(11):3941–3951. doi: 10.1002/j.1460-2075.1992.tb05488.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Richardson J. M., Morla A. O., Wang J. Y. Reduction in protein tyrosine phosphorylation during differentiation of human leukemia cell line K-562. Cancer Res. 1987 Aug 1;47(15):4066–4070. [PubMed] [Google Scholar]
  48. Ryseck R. P., Hirai S. I., Yaniv M., Bravo R. Transcriptional activation of c-jun during the G0/G1 transition in mouse fibroblasts. Nature. 1988 Aug 11;334(6182):535–537. doi: 10.1038/334535a0. [DOI] [PubMed] [Google Scholar]
  49. Scharfmann R., Axelrod J. H., Verma I. M. Long-term in vivo expression of retrovirus-mediated gene transfer in mouse fibroblast implants. Proc Natl Acad Sci U S A. 1991 Jun 1;88(11):4626–4630. doi: 10.1073/pnas.88.11.4626. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Schultz A., Oroszlan S. Myristylation of gag-onc fusion proteins in mammalian transforming retroviruses. Virology. 1984 Mar;133(2):431–437. doi: 10.1016/0042-6822(84)90409-4. [DOI] [PubMed] [Google Scholar]
  51. Schwartz M. A. Signaling by integrins: implications for tumorigenesis. Cancer Res. 1993 Apr 1;53(7):1503–1506. [PubMed] [Google Scholar]
  52. Shaw R. J., Doherty D. E., Ritter A. G., Benedict S. H., Clark R. A. Adherence-dependent increase in human monocyte PDGF(B) mRNA is associated with increases in c-fos, c-jun, and EGR2 mRNA. J Cell Biol. 1990 Nov;111(5 Pt 1):2139–2148. doi: 10.1083/jcb.111.5.2139. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Shoemaker C., Hoffman J., Goff S. P., Baltimore D. Intramolecular integration within Moloney murine leukemia virus DNA. J Virol. 1981 Oct;40(1):164–172. doi: 10.1128/jvi.40.1.164-172.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Stokoe D., Macdonald S. G., Cadwallader K., Symons M., Hancock J. F. Activation of Raf as a result of recruitment to the plasma membrane. Science. 1994 Jun 3;264(5164):1463–1467. doi: 10.1126/science.7811320. [DOI] [PubMed] [Google Scholar]
  55. Upadhyaya G., Guba S. C., Sih S. A., Feinberg A. P., Talpaz M., Kantarjian H. M., Deisseroth A. B., Emerson S. G. Interferon-alpha restores the deficient expression of the cytoadhesion molecule lymphocyte function antigen-3 by chronic myelogenous leukemia progenitor cells. J Clin Invest. 1991 Dec;88(6):2131–2136. doi: 10.1172/JCI115543. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Verfaillie C. M. Direct contact between human primitive hematopoietic progenitors and bone marrow stroma is not required for long-term in vitro hematopoiesis. Blood. 1992 Jun 1;79(11):2821–2826. [PubMed] [Google Scholar]
  57. Wang J. Y. Isolation of antibodies for phosphotyrosine by immunization with a v-abl oncogene-encoded protein. Mol Cell Biol. 1985 Dec;5(12):3640–3643. doi: 10.1128/mcb.5.12.3640. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Wang J. Y. Modelling chronic myelogenous leukemia. Curr Biol. 1992 Feb;2(2):70–72. doi: 10.1016/0960-9822(92)90198-j. [DOI] [PubMed] [Google Scholar]
  59. Wood K. W., Sarnecki C., Roberts T. M., Blenis J. ras mediates nerve growth factor receptor modulation of three signal-transducing protein kinases: MAP kinase, Raf-1, and RSK. Cell. 1992 Mar 20;68(6):1041–1050. doi: 10.1016/0092-8674(92)90076-o. [DOI] [PubMed] [Google Scholar]
  60. Young J. C., Witte O. N. Selective transformation of primitive lymphoid cells by the BCR/ABL oncogene expressed in long-term lymphoid or myeloid cultures. Mol Cell Biol. 1988 Oct;8(10):4079–4087. doi: 10.1128/mcb.8.10.4079. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. 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]
  62. de Wet J. R., Wood K. V., DeLuca M., Helinski D. R., Subramani S. Firefly luciferase gene: structure and expression in mammalian cells. Mol Cell Biol. 1987 Feb;7(2):725–737. doi: 10.1128/mcb.7.2.725. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. van Zonneveld A. J., Curriden S. A., Loskutoff D. J. Type 1 plasminogen activator inhibitor gene: functional analysis and glucocorticoid regulation of its promoter. Proc Natl Acad Sci U S A. 1988 Aug;85(15):5525–5529. doi: 10.1073/pnas.85.15.5525. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Molecular and Cellular Biology are provided here courtesy of Taylor & Francis

RESOURCES