Skip to main content
PMC home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1994 Mar 1;179(3):999–1004. doi: 10.1084/jem.179.3.999

Transforming growth factor beta as endogenous growth inhibitor of chronic lymphocytic leukemia B cells

PMCID: PMC2191408  PMID: 8113691

Abstract

Chronic lymphocytic leukemia (CLL) B cells are hyporesponsive or refractory to mitogens and growth factors in vitro. This study examined whether transforming growth factor beta (TGF-beta), a potent inhibitor of lymphocyte proliferation may play a role in the growth regulation of CLL B cells. CLL B cells from all donors treated expressed detectable TGF-beta 1 mRNA. In vitro release of TGF-beta by unstimulated cultures, or cultures stimulated by antibody to cell surface immunoglobulin (anti- mu) plus phorbol 12-myristate 13-acetate (PMA) was higher in CLL than in normal B cells. High levels of TGF-beta activity were also detected in plasma samples of CLL patients. The role of TGF-beta in growth regulation of CLL B cells was tested in assays using different B cell activators. Purified neoplastic B cells from most CLL patients proliferated in response to anti-mu, or the combination of anti-mu plus PMA. Levels of CLL B cell proliferation were lower than observed in normal B cells. Some CLL were refractory to these stimuli. Antibody to CD40 induced proliferation of CLL B cells from all donors tested when presented on Fc gamma RII (CDw32)-expressing L cells. Neutralizing antibodies to TGF-beta increased CLL B cell proliferation in the absence or presence of additional stimuli. These effects were dose dependent and specific. Exogenous TGF-beta completely inhibited CLL B cell proliferation induced by anti-mu, PMA, and anti-TGF-beta. CLL B cell proliferation induced by anti-CD40 was reduced by exogenous TGF- beta. However, even at high doses, TGF-beta did not completely inhibit the anti-CD40 effect. In summary, TGF-beta is overexpressed in CLL. CLL B cells are sensitive to TGF-beta and this cytokine functions as an autocrine growth inhibitor accounting at least in part for reduced proliferative responses of these leukemic cells and for the slow progression of the malignant process in vivo.

Full Text

The Full Text of this article is available as a PDF (487.8 KB).

Selected References

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

  1. Dadmarz R., Rabinowe S. N., Cannistra S. A., Andersen J. W., Freedman A. S., Nadler L. M. Association between clonogenic cell growth and clinical risk group in B-cell chronic lymphocytic leukemia. Blood. 1990 Jul 1;76(1):142–149. [PubMed] [Google Scholar]
  2. Digel W., Schmid M., Heil G., Conrad P., Gillis S., Porzsolt F. Human interleukin-7 induces proliferation of neoplastic cells from chronic lymphocytic leukemia and acute leukemias. Blood. 1991 Aug 1;78(3):753–759. [PubMed] [Google Scholar]
  3. Fluckiger A. C., Rossi J. F., Bussel A., Bryon P., Banchereau J., Defrance T. Responsiveness of chronic lymphocytic leukemia B cells activated via surface Igs or CD40 to B-cell tropic factors. Blood. 1992 Dec 15;80(12):3173–3181. [PubMed] [Google Scholar]
  4. Foa R., Massaia M., Cardona S., Tos A. G., Bianchi A., Attisano C., Guarini A., di Celle P. F., Fierro M. T. Production of tumor necrosis factor-alpha by B-cell chronic lymphocytic leukemia cells: a possible regulatory role of TNF in the progression of the disease. Blood. 1990 Jul 15;76(2):393–400. [PubMed] [Google Scholar]
  5. Foon K. A., Rai K. R., Gale R. P. Chronic lymphocytic leukemia: new insights into biology and therapy. Ann Intern Med. 1990 Oct 1;113(7):525–539. doi: 10.7326/0003-4819-113-7-525. [DOI] [PubMed] [Google Scholar]
  6. Ghaderi A. A., Richardson P., Cardona C., Millsum M. J., Ling N., Gillis S., Ledbetter J., Gordon J. Stimulation of B-chronic lymphocytic leukemia populations by recombinant interleukin-4 and other defined growth-promoting agents. Leukemia. 1988 Mar;2(3):165–170. [PubMed] [Google Scholar]
  7. Gordon J., Katira A., Strain A. J., Gillis S. Inhibition of interleukin 4-promoted CD23 production in human B lymphocytes by transforming growth factor-beta, interferons or anti-CD19 antibody is overriden on engaging CD40. Eur J Immunol. 1991 Aug;21(8):1917–1922. doi: 10.1002/eji.1830210821. [DOI] [PubMed] [Google Scholar]
  8. Hivroz C., Fischer E., Kazatchkine M. D., Grillot-Courvalin C. Differential effects of the stimulation of complement receptors CR1 (CD35) and CR2 (CD21) on cell proliferation and intracellular Ca2+ mobilization of chronic lymphocytic leukemia B cells. J Immunol. 1991 Mar 15;146(6):1766–1772. [PubMed] [Google Scholar]
  9. Kehrl J. H., Taylor A., Kim S. J., Fauci A. S. Transforming growth factor-beta is a potent negative regulator of human lymphocytes. Ann N Y Acad Sci. 1991;628:345–353. doi: 10.1111/j.1749-6632.1991.tb17267.x. [DOI] [PubMed] [Google Scholar]
  10. Kekow J., Wachsman W., McCutchan J. A., Cronin M., Carson D. A., Lotz M. Transforming growth factor beta and noncytopathic mechanisms of immunodeficiency in human immunodeficiency virus infection. Proc Natl Acad Sci U S A. 1990 Nov;87(21):8321–8325. doi: 10.1073/pnas.87.21.8321. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Kipps T. J., Meisenholder G., Robbins B. A. New developments in flow cytometric analyses of lymphocyte markers. Clin Lab Med. 1992 Jun;12(2):237–275. [PubMed] [Google Scholar]
  12. Kremer J. P., Reisbach G., Nerl C., Dörmer P. B-cell chronic lymphocytic leukaemia cells express and release transforming growth factor-beta. Br J Haematol. 1992 Apr;80(4):480–487. doi: 10.1111/j.1365-2141.1992.tb04561.x. [DOI] [PubMed] [Google Scholar]
  13. Lotz M., Kekow J., Carson D. A. Transforming growth factor-beta and cellular immune responses in synovial fluids. J Immunol. 1990 Jun 1;144(11):4189–4194. [PubMed] [Google Scholar]
  14. Niitsu Y., Urushizaki Y., Koshida Y., Terui K., Mahara K., Kohgo Y., Urushizaki I. Expression of TGF-beta gene in adult T cell leukemia. Blood. 1988 Jan;71(1):263–266. [PubMed] [Google Scholar]
  15. Rai K. R., Sawitsky A., Cronkite E. P., Chanana A. D., Levy R. N., Pasternack B. S. Clinical staging of chronic lymphocytic leukemia. Blood. 1975 Aug;46(2):219–234. [PubMed] [Google Scholar]
  16. Ranheim E. A., Kipps T. J. Activated T cells induce expression of B7/BB1 on normal or leukemic B cells through a CD40-dependent signal. J Exp Med. 1993 Apr 1;177(4):925–935. doi: 10.1084/jem.177.4.925. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Zaknoen S. L., Kay N. E. Immunoregulatory cell dysfunction in chronic B-cell leukemias. Blood Rev. 1990 Sep;4(3):165–174. doi: 10.1016/0268-960x(90)90044-s. [DOI] [PubMed] [Google Scholar]
  18. van Kooten C., Rensink I., Aarden L., van Oers R. Interleukin-4 inhibits both paracrine and autocrine tumor necrosis factor-alpha-induced proliferation of B chronic lymphocytic leukemia cells. Blood. 1992 Sep 1;80(5):1299–1306. [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES