Aberrant responses of human lymphocytic neoplasms to cytokine regulation
- 34 Downloads
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 wordsApoptosis Chronic lymphocytic leukemia Cytokines TGF-beta
Unable to display preview. Download preview PDF.
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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