Immunologic Research

, Volume 17, Issue 1–2, pp 171–177 | Cite as

Aberrant responses of human lymphocytic neoplasms to cytokine regulation



Studies in this laboratory have recently focused on two hemic neoplasms: B cell chronic lymphocytic leukemia (B-CLL) and a T cell disorder, Sézary syndrome. These tumors do not have consistent cytogenetic or molecular genetic alterations, and so we have concentrated on their response to and production of various regulatory cytokines. Although B-CLL cells show variable proliferative responses when exposed to transforming growth factor beta (TGFΒ), these cells have consistently shown resistance to the proapoptotic effects of this cytokine. Also, interleukin 4 (IL4), IL5, and interferon-gamma (IFNγ) all show a consistently increased protective effect against apoptosis in B-CLL cells as compared to normal human B cells. Thus, a defect in apoptosis appears to be an important factor in the pathogenesis of CLL. By contrast, the neoplastic T cells of Sézary syndrome show a consistent resistance to the antiproliferative effects of TGFΒ, suggesting that aberrant proliferation is more important than apoptosis in this disorder. In both neoplasms, we have shown that the defective responses to cytokines are in some instances related to alterations in receptor expression, but this has not been true in all circumstances, and other stages in the signaling pathways are being investigated. As we define more precisely the specific defects that contribute to the clonal expansion of these neoplasms, the findings may ultimately lead to improved clinical control of these disorders.

Key words

Apoptosis Chronic lymphocytic leukemia Cytokines TGF-beta 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Nowell PC: Genetic alterations in leukemias and lymphomas: impressive progress and continuing complexity. Cancer Genet Cytogenet 1997;94:13–20.PubMedCrossRefGoogle Scholar
  2. 2.
    Moore JS, Friedman DF, Silberstein LE, Besa EC, Nowell PC: Clinical heterogeneity reflects biologic diversity in chronic lymphocytic leukemia. Crit Rev Oncol Hematol 1995;20:141–164.PubMedCrossRefGoogle Scholar
  3. 3.
    Marks DI, Vonderheid EC, Kurz BW, Bigler RD, Sinha K, Morgan DA, et al.: Analysis of p53 and mdm-2 expression in 18 patients with Sézary syndrome. Br J Haematol 1996;92:890–899.PubMedCrossRefGoogle Scholar
  4. 4.
    Thangavelu M, Finn WG, Yelavarthi KK, Roenigk HH, Samuelson E, Peterson LA, et al.: Recurring structural chromosome abnormalities in peripheral blood lymphocytes of patients with mycosis fungoides/Sézary syndrome. Blood 1997;89:3371–3377.PubMedGoogle Scholar
  5. 5.
    Kerhl JH, Roberts AB, Wakefield LM, Jakowlew SB, Sporn MB, Fauci AS:Transforming growth factor beta is an important immunomodulatory protein for human B lymphocytes. J Immunol 1986; 137:3855–3859.Google Scholar
  6. 6.
    Wahl SM, Hunt DA, Wong HL, Doughert S, McCartney-Francis N, Wahl LM, et al.: Transforming growth factor beta is a potent immunosuppressive agent that inhibits IL-1 dependent lymphocyte proliferation. J Immunol 1988;140:3026–3030.PubMedGoogle Scholar
  7. 7.
    Chaouchi N, Arvanitakis L, Auffredou MT, Blanchard DA, Vazquez A, Sharma S: Characterization of transforming growth factor-beta-1 induced apoptosis in normal human B-cells and lymphoma B-cell lines. Oncogene 1995;11:1615–1620.PubMedGoogle Scholar
  8. 8.
    Trentin L, Cerutti A, Zambello R, Sancetta R, Tassinari C, Facco M, et al.: Interleukin-15 promotes the growth of leukemic cells of patients with B-cell chronic lymphoproliferative disorders. Blood 1996;87: 3327–3335.PubMedGoogle Scholar
  9. 9.
    Osario LM, De Santiago A, Aguilar-Santalises M, Mellstedt H, Jondal M: CD6 ligation modulates the Bcl-2/Bax ratio and protects chronic lymphocytic leukemia B-cells from apoptosis induced by anti-IgM. Blood 1997;89:2833–2841.Google Scholar
  10. 10.
    Rook AH, Kubin M, Cassin M, Vonderheid EC, Vowels BR, Wolfe JT, Wolf SF, Singh A, Trinchieri G, Lessin SR:IL-12 reverses cytokine and immune abnormalities in Sezary syndrome. J Immunol 1995;154:1491–1498.PubMedGoogle Scholar
  11. 11.
    McCusker ME, Garifallou M, Bogen SA: Sezary lineage cells can be induced to proliferate via CD28-mediated costimulation. J Immunol 1997;158:4984–4991.PubMedGoogle Scholar
  12. 12.
    Mauer AM: Clinical features of human leukemia; in Mauer AM (ed): The Biology of Human Leukemia. Baltimore, Johns Hopkins University Press, 1990, pp 1–27.Google Scholar
  13. 13.
    Douglas RS, Capocasale RJ, Lamb RJ, Nowell PC, Moore JS: Chronic lymphocytic leukemia B-cells are resistant to the apoptotic effects of transforming growth factor-beta. Blood;1997:89:941–947.PubMedGoogle Scholar
  14. 14.
    Kremer JP, Reisbach G, Nerl C, Dormer P: B-cell chronic lymphocytic leukaemia cells express and release transforming growth factor -beta. Br J Haematol 1992;80: 480–489.PubMedGoogle Scholar
  15. 15.
    Lotz M, Raanhein E, Kipps T:Transforming growth factor beta as endogenous growth inhibitor of chronic lymphocytic leukemia B-cells. J Exp Med 1994;179:999–1008.PubMedCrossRefGoogle Scholar
  16. 16.
    DeCoteau JF, Knaus PI, Yankelev H, Reis MD, Lowsky R, Lodish HF, et al.:Loss of functional cell surface transforming growth factor beta (TGF-Β) type l receptor correlates with insensitivity to TGFΒ in chronic lymphocytic leukemia. Proc Natl Acad Sci USA 1997; 94:5877–5881.PubMedCrossRefGoogle Scholar
  17. 17.
    Phillips JA, Mehta K, Fernandez C, Raveche ES: The NZB mouse as a model for chronic lymphocytic leukemia. Cancer Res 1992; 52:437–443.PubMedGoogle Scholar
  18. 18.
    Phillips J, Raveche E: Immunoregulatory capability of murine CLL-like CD5+ B-cells. Ann NY Acad Sci 1992;651:488–490.PubMedCrossRefGoogle Scholar
  19. 19.
    Raveche ES, Lalor P, Stall A, Conroy J: In vivo effects of hyperdiploid Ly-1+ B-cells of NZB origin. J Immunol 1988:141:4133–4139.PubMedGoogle Scholar
  20. 20.
    Douglas RS, Woo EY, Capocasale RJ, Tarshis AD, Nowell PC, Moore SJ: Altered response to and production of TGF-\ by B-cells from autoimmune NZB mice. Cell Immunol 1997;179:126–131.PubMedCrossRefGoogle Scholar
  21. 21.
    Dancescu M, Rubio-Trujillo M, Biron G, Bron D, Delespesse G, Sarfati M: Interleukin-4 protects chronic lymphocytic leukemia from death by apoptosis and upregulates Bcl-2 expression. J Exp Med 1992;176:1319–1329.PubMedCrossRefGoogle Scholar
  22. 22.
    Panayiotidis P, Ganeshaguru K, Jabbar SAB, Hoffbrand AV:IL-4 inhibits apoptotic cell death and loss of the Bcl-2 protein in B-CLL cells in vitro. Br J Haematol 1993; 85:439–451.PubMedCrossRefGoogle Scholar
  23. 23.
    Moore JS, Zaki M, Douglas R, Nowell P: Altered cytokine production by T cells from patients with B-CLL (Abstract). Cytometry 1997, in press.Google Scholar
  24. 24.
    Buschle M, Campana D, Carding S, Richard C, Hoffbrand AV, Brenner MK: Interferon-gamma inhibits apoptotic cell death in B-cell chronic lymphocytic leukemia. J Exp Med 1993;177:213–218.PubMedCrossRefGoogle Scholar
  25. 25.
    Kobayashi R, Rassenti LZ, Meisenholder G, Carson DA, Kipps TJ: Autoantigen inhibits apoptosis of a human B-cell leukemia that produces pathogenic rheumatoid factor. J Immunol 1993;151:7273–7283.PubMedGoogle Scholar
  26. 26.
    Rabbitts T: Translocations, master genes and differences between the origins of acute and chronic leukemias. Cell 1991;67:641–653.PubMedCrossRefGoogle Scholar
  27. 27.
    Kitada S, Bullrich F, Krajewski S, Zapata J, Andersen J, Hines J, et al.: Bcl-2 family genes, CPP32 protease, 13ql4 deletions, and in vitro sensitivity to fludarabine and 2-chlorodeoxyadenosine in B-CLL: an ECOG study [Abstract]. Proc Am Assoc Cancer Res 1997;38:169.Google Scholar
  28. 28.
    Krajewski S, Gascoyne RD, Zapata JM, Krajewska M, Kitada S, Chhanabhai M, et al.: Immunolocalization of the ICE/Ced-3-family protease, CPP32 (Caspase-3), in non-Hodgkin’s lymphomas, chronic lymphocytic leukemias, and reactive lymph nodes. Blood 1997;89:3817–3825.PubMedGoogle Scholar
  29. 29.
    Karras JG, Wang Z, Huo L, Howard RG, Frank DA, Rothstein TL: Signal transducer and activator of transcription-3 (STAT3) is constitutively activated in normal, selfrenewing B-l cells but only inducibly expressed in conventional B lymphocytes. J Exp Med. 1997;185:1035–1042.PubMedCrossRefGoogle Scholar
  30. 30.
    Bellosillo B, Dalmau M, Colomer D, Gil J: Involvement of CED-3/ ICE proteases in the apoptosis of B-chronic lymphocytic leukemia cells. Blood 1997;89:3378–3384.PubMedGoogle Scholar
  31. 31.
    Sterry W, Mielke V: CD4+ cutaneous T cell lymphomas show the phenotype of helper/inducer T-cells (CD45RA-,CDw29+). J Invest Dermatol 1989;93:413–416.PubMedCrossRefGoogle Scholar
  32. 32.
    Heald P, Yan S-L, Edelson R: Profound deficiency in normal circulating T-cells in erythrodermic cutaneous T-cell lymphoma. Arch Dermatol 1994;130:198–203.PubMedCrossRefGoogle Scholar
  33. 33.
    Bogen SA, Pelley D, Charif M, McCusker M, Koh H, Foss F, et al.: Immunophenotypic identification of Sezary’s cells in peripheral blood. Am J Clin Pathol 1996; 106:739–747.PubMedGoogle Scholar
  34. 34.
    Edelson RL: Cutaneous T-cell lymphoma: mycosis fungoides, Sezary syndrome, and other variants. J Am Acad Dermatol 1980;2:89:106.PubMedGoogle Scholar
  35. 35.
    Capocasale RJ, Lamb RJ, VonDerheid EC, Fox FE, Rook AH, Nowell PC, et al.: Reduced surface expression of transforming growth factor beta receptor type II in mitogen-activated T-cells from Sézary patients. Proc Natl Acad Sci USA 1995;92:5501–5505.PubMedCrossRefGoogle Scholar
  36. 36.
    Kadin ME, Cavaille-Coll MW, Gertz R, Massague J, Cheifetz S, George D:Loss of receptors for transforming growth factor beta in human T-cell malignancies. Proc Natl Acad Sci USA 1994;91:6002–6006.PubMedCrossRefGoogle Scholar
  37. 37.
    Myeroff LL, Parsons R, Kim S-J, Hedrick L, Cho KR, Orth K, et al.: A transforming growth factor beta receptor type II gene mutation common in colon and gastric but rare in endometrial cancers with microsatellite instability. Cancer Res 1995;55:5545–5547.PubMedGoogle Scholar
  38. 38.
    Zhang Q, Nowak I, Vonderheid EC, Rook AH, Kadin ME, Nowell PC, et al.: Activation of Jak/STAT proteins involved in signal transduction pathway mediated by receptor for interleukin 2 in malignant T lymphocytes derived from cutaneous anaplastic large T-cell lymphoma and Sezary syndrome. Proc Natl Acad Sci USA 1996;93:9148–9153.PubMedCrossRefGoogle Scholar

Copyright information

© Human Press Inc 1998

Authors and Affiliations

  1. 1.Department of Pathology and Laboratory MedicineUniversity of Pennsylvania School of MedicinePhiladelphia

Personalised recommendations