Abstract
Regulation of expression of interleukin 7 (IL-7) mRNA is aberrant in the leukemic subset of cells of chronic lymphocytic leukemia (CLL) patients. The entire coding sequence for IL-7 as well as an alternatively spliced IL-7 mRNA are transcribed in these leukemic cells. No IL-7 mRNA expression is detected in fresh peripheral blood mononuclear cells from normal individuals. Furthermore, the "normal" nonleukemic subsets of cells isolated from the same CLL patients also do not express IL-7 mRNA. The only subset of cells in which IL-7 mRNA is detected is the one that contains the leukemic cells themselves. The polymerase chain reaction was used to examine cytokine expression, and flow cytometry was used to purify the various subsets of peripheral blood mononuclear cells examined in these studies, as well as to examine IL-7 receptor expression. A proportion of the cells from the CLL patients express receptors that are capable of binding IL-7, whereas T cell-depleted normal cell preparations do not express receptors for IL-7 that are detectable with IL-7 fluorokines. The IL-7 receptor-bearing cells in CLL patients include a portion of leukemic cells and a fraction of the T cells, as well as some non-T, non-B cells. These findings suggest that IL-7 and IL-7 receptor expression in CLL may be relevant not only to growth regulation of the leukemic cells but to the immunological abnormalities that occur in the disease as well, possibly via the induction of inappropriate immune activity of IL- 7 receptor-bearing cells.
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- Biondi A., Rossi V., Bassan R., Barbui T., Bettoni S., Sironi M., Mantovani A., Rambaldi A. Constitutive expression of the interleukin-6 gene in chronic lymphocytic leukemia. Blood. 1989 Apr;73(5):1279–1284. [PubMed] [Google Scholar]
- Casali P., Notkins A. L. Probing the human B-cell repertoire with EBV: polyreactive antibodies and CD5+ B lymphocytes. Annu Rev Immunol. 1989;7:513–535. doi: 10.1146/annurev.iy.07.040189.002501. [DOI] [PubMed] [Google Scholar]
- Chiorazzi N., Fu S. M., Montazeri G., Kunkel H. G., Rai K., Gee T. T cell helper defect in patients with chronic lymphocytic leukemia. J Immunol. 1979 Mar;122(3):1087–1090. [PubMed] [Google Scholar]
- Chirgwin J. M., Przybyla A. E., MacDonald R. J., Rutter W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
- Cleary M. L., Chao J., Warnke R., Sklar J. Immunoglobulin gene rearrangement as a diagnostic criterion of B-cell lymphoma. Proc Natl Acad Sci U S A. 1984 Jan;81(2):593–597. doi: 10.1073/pnas.81.2.593. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cordingley F. T., Bianchi A., Hoffbrand A. V., Reittie J. E., Heslop H. E., Vyakarnam A., Turner M., Meager A., Brenner M. K. Tumour necrosis factor as an autocrine tumour growth factor for chronic B-cell malignancies. Lancet. 1988 Apr 30;1(8592):969–971. doi: 10.1016/s0140-6736(88)91782-5. [DOI] [PubMed] [Google Scholar]
- Dibirdik I., Langlie M. C., Ledbetter J. A., Tuel-Ahlgren L., Obuz V., Waddick K. G., Gajl-Peczalska K., Schieven G. L., Uckun F. M. Engagement of interleukin-7 receptor stimulates tyrosine phosphorylation, phosphoinositide turnover, and clonal proliferation of human T-lineage acute lymphoblastic leukemia cells. Blood. 1991 Aug 1;78(3):564–570. [PubMed] [Google Scholar]
- 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]
- Ennis P. D., Zemmour J., Salter R. D., Parham P. Rapid cloning of HLA-A,B cDNA by using the polymerase chain reaction: frequency and nature of errors produced in amplification. Proc Natl Acad Sci U S A. 1990 Apr;87(7):2833–2837. doi: 10.1073/pnas.87.7.2833. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gadol N., Ault K. A. Phenotypic and functional characterization of human Leu1 (CD5) B cells. Immunol Rev. 1986 Oct;93:23–34. doi: 10.1111/j.1600-065x.1986.tb01500.x. [DOI] [PubMed] [Google Scholar]
- Gale R. P., Foon K. A. Chronic lymphocytic leukemia. Recent advances in biology and treatment. Ann Intern Med. 1985 Jul;103(1):101–120. doi: 10.7326/0003-4819-103-1-101. [DOI] [PubMed] [Google Scholar]
- Goodwin R. G., Lupton S., Schmierer A., Hjerrild K. J., Jerzy R., Clevenger W., Gillis S., Cosman D., Namen A. E. Human interleukin 7: molecular cloning and growth factor activity on human and murine B-lineage cells. Proc Natl Acad Sci U S A. 1989 Jan;86(1):302–306. doi: 10.1073/pnas.86.1.302. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hahn T., Kusminsky G., Bassous L., Barak Y., Berrebi A. Tumour necrosis factor in B chronic lymphocytic leukaemia. Br J Haematol. 1989 Feb;71(2):299–299. doi: 10.1111/j.1365-2141.1989.tb04275.x. [DOI] [PubMed] [Google Scholar]
- Hayakawa K., Hardy R. R., Honda M., Herzenberg L. A., Steinberg A. D., Herzenberg L. A. Ly-1 B cells: functionally distinct lymphocytes that secrete IgM autoantibodies. Proc Natl Acad Sci U S A. 1984 Apr;81(8):2494–2498. doi: 10.1073/pnas.81.8.2494. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Henney C. S. Interleukin 7: effects on early events in lymphopoiesis. Immunol Today. 1989 May;10(5):170–173. doi: 10.1016/0167-5699(89)90175-8. [DOI] [PubMed] [Google Scholar]
- Hock H., Dorsch M., Diamantstein T., Blankenstein T. Interleukin 7 induces CD4+ T cell-dependent tumor rejection. J Exp Med. 1991 Dec 1;174(6):1291–1298. doi: 10.1084/jem.174.6.1291. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jicha D. L., Mulé J. J., Rosenberg S. A. Interleukin 7 generates antitumor cytotoxic T lymphocytes against murine sarcomas with efficacy in cellular adoptive immunotherapy. J Exp Med. 1991 Dec 1;174(6):1511–1515. doi: 10.1084/jem.174.6.1511. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kawamura N., Muraguchi A., Hori A., Horii Y., Mutsuura S., Hardy R. R., Kikutani H., Kishimoto T. A case of human B cell leukemia that implicates an autocrine mechanism in the abnormal growth of Leu 1 B cells. J Clin Invest. 1986 Nov;78(5):1331–1338. doi: 10.1172/JCI112719. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kay N. E. Abnormal T-cell subpopulation function in CLL: excessive suppressor (T gamma) and deficient helper (T mu) activity with respect to B-cell proliferation. Blood. 1981 Mar;57(3):418–420. [PubMed] [Google Scholar]
- Kay N. E., Burton J., Wagner D., Nelson D. L. The malignant B cells from B-chronic lymphocytic leukemia patients release TAC-soluble interleukin-2 receptors. Blood. 1988 Aug;72(2):447–450. [PubMed] [Google Scholar]
- Lupton S. D., Gimpel S., Jerzy R., Brunton L. L., Hjerrild K. A., Cosman D., Goodwin R. G. Characterization of the human and murine IL-7 genes. J Immunol. 1990 May 1;144(9):3592–3601. [PubMed] [Google Scholar]
- Lynch D. H., Namen A. E., Miller R. E. In vivo evaluation of the effects of interleukins 2, 4 and 7 on enhancing the immunotherapeutic efficacy of anti-tumor cytotoxic T lymphocytes. Eur J Immunol. 1991 Dec;21(12):2977–2985. doi: 10.1002/eji.1830211212. [DOI] [PubMed] [Google Scholar]
- Masuda M., Takanashi M., Motoji T., Oshimi K., Mizoguchi H. Effects of interleukins 1-7 on the proliferation of T-lineage acute lymphoblastic leukemia cells. Leuk Res. 1991;15(12):1091–1096. doi: 10.1016/0145-2126(91)90176-t. [DOI] [PubMed] [Google Scholar]
- Mercolino T. J., Arnold L. W., Haughton G. Phosphatidyl choline is recognized by a series of Ly-1+ murine B cell lymphomas specific for erythrocyte membranes. J Exp Med. 1986 Jan 1;163(1):155–165. doi: 10.1084/jem.163.1.155. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Moore J. S., Prystowsky M. B., Hoover R. G., Besa E. C., Nowell P. C. Defective T cell-mediated, isotype-specific immunoglobulin regulation in B cell chronic lymphocytic leukemia. Blood. 1988 Apr;71(4):1012–1020. [PubMed] [Google Scholar]
- Morabito F., Prasthofer E. F., Dunlap N. E., Grossi C. E., Tilden A. B. Expression of myelomonocytic antigens on chronic lymphocytic leukemia B cells correlates with their ability to produce interleukin 1. Blood. 1987 Dec;70(6):1750–1757. [PubMed] [Google Scholar]
- Namen A. E., Lupton S., Hjerrild K., Wignall J., Mochizuki D. Y., Schmierer A., Mosley B., March C. J., Urdal D., Gillis S. Stimulation of B-cell progenitors by cloned murine interleukin-7. Nature. 1988 Jun 9;333(6173):571–573. doi: 10.1038/333571a0. [DOI] [PubMed] [Google Scholar]
- Namen A. E., Schmierer A. E., March C. J., Overell R. W., Park L. S., Urdal D. L., Mochizuki D. Y. B cell precursor growth-promoting activity. Purification and characterization of a growth factor active on lymphocyte precursors. J Exp Med. 1988 Mar 1;167(3):988–1002. doi: 10.1084/jem.167.3.988. [DOI] [PMC free article] [PubMed] [Google Scholar]
- O'Garra A., Stapleton G., Dhar V., Pearce M., Schumacher J., Rugo H., Barbis D., Stall A., Cupp J., Moore K. Production of cytokines by mouse B cells: B lymphomas and normal B cells produce interleukin 10. Int Immunol. 1990;2(9):821–832. doi: 10.1093/intimm/2.9.821. [DOI] [PubMed] [Google Scholar]
- Pistoia V., Cozzolino F., Rubartelli A., Torcia M., Roncella S., Ferrarini M. In vitro production of interleukin 1 by normal and malignant human B lymphocytes. J Immunol. 1986 Mar 1;136(5):1688–1692. [PubMed] [Google Scholar]
- Platsoucas C. D., Galinski M., Kempin S., Reich L., Clarkson B., Good R. A. Abnormal T lymphocyte subpopulations in patients with B cell chronic lymphocytic leukemia: an analysis by monoclonal antibodies. J Immunol. 1982 Nov;129(5):2305–2312. [PubMed] [Google Scholar]
- Rangnekar V. M., Thomas L. S., Plate J. M. Immunoprecipitation of interleukin-1 receptors from a mouse thymoma cell line, EL-4. J Biol Chem. 1988 Nov 5;263(31):16408–16413. [PubMed] [Google Scholar]
- Ravetch J. V., Siebenlist U., Korsmeyer S., Waldmann T., Leder P. Structure of the human immunoglobulin mu locus: characterization of embryonic and rearranged J and D genes. Cell. 1981 Dec;27(3 Pt 2):583–591. doi: 10.1016/0092-8674(81)90400-1. [DOI] [PubMed] [Google Scholar]
- Roudier J., Silverman G. J., Chen P. P., Carson D. A., Kipps T. J. Intraclonal diversity in the VH genes expressed by CD5- chronic lymphocytic leukemia-producing pathologic IgM rheumatoid factor. J Immunol. 1990 Feb 15;144(4):1526–1530. [PubMed] [Google Scholar]
- Semenzato G., Foa R., Agostini C., Zambello R., Trentin L., Vinante F., Benedetti F., Chilosi M., Pizzolo G. High serum levels of soluble interleukin 2 receptor in patients with B chronic lymphocytic leukemia. Blood. 1987 Aug;70(2):396–400. [PubMed] [Google Scholar]
- Smyth M. J., Norihisa Y., Gerard J. R., Young H. A., Ortaldo J. R. IL-7 regulation of cytotoxic lymphocytes: pore-forming protein gene expression, interferon-gamma production, and cytotoxicity of human peripheral blood lymphocytes subsets. Cell Immunol. 1991 Dec;138(2):390–403. doi: 10.1016/0008-8749(91)90163-6. [DOI] [PubMed] [Google Scholar]
- Soper L., Bernhardt B., Eisenberg A., Cacciapaglia B., Bennett L., Sanda A., Baird M., Silver R., Benn P. Clonal immunoglobulin gene rearrangements in chronic lymphocytic leukemia: a correlative study. Am J Hematol. 1988 Apr;27(4):257–264. doi: 10.1002/ajh.2830270406. [DOI] [PubMed] [Google Scholar]
- Southern E. M. Detection of specific sequences among DNA fragments separated by gel electrophoresis. J Mol Biol. 1975 Nov 5;98(3):503–517. doi: 10.1016/s0022-2836(75)80083-0. [DOI] [PubMed] [Google Scholar]
- Stall A. M., Fariñas M. C., Tarlinton D. M., Lalor P. A., Herzenberg L. A., Strober S., Herzenberg L. A. Ly-1 B-cell clones similar to human chronic lymphocytic leukemias routinely develop in older normal mice and young autoimmune (New Zealand Black-related) animals. Proc Natl Acad Sci U S A. 1988 Oct;85(19):7312–7316. doi: 10.1073/pnas.85.19.7312. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sthoeger Z. M., Wakai M., Tse D. B., Vinciguerra V. P., Allen S. L., Budman D. R., Lichtman S. M., Schulman P., Weiselberg L. R., Chiorazzi N. Production of autoantibodies by CD5-expressing B lymphocytes from patients with chronic lymphocytic leukemia. J Exp Med. 1989 Jan 1;169(1):255–268. doi: 10.1084/jem.169.1.255. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Touw I., Pouwels K., van Agthoven T., van Gurp R., Budel L., Hoogerbrugge H., Delwel R., Goodwin R., Namen A., Löwenberg B. Interleukin-7 is a growth factor of precursor B and T acute lymphoblastic leukemia. Blood. 1990 Jun 1;75(11):2097–2101. [PubMed] [Google Scholar]
- Tötterman T. H., Carlsson M., Simonsson B., Bengtsson M., Nilsson K. T-cell activation and subset patterns are altered in B-CLL and correlate with the stage of the disease. Blood. 1989 Aug 1;74(2):786–792. [PubMed] [Google Scholar]
- Uggla C., Aguilar-Santelises M., Rosén A., Mellstedt H., Jondal M. Spontaneous production of interleukin 1 activity by chronic lymphocytic leukemic cells. Blood. 1987 Dec;70(6):1851–1857. [PubMed] [Google Scholar]
- Welch P. A., Namen A. E., Goodwin R. G., Armitage R., Cooper M. D. Human IL-7: a novel T cell growth factor. J Immunol. 1989 Dec 1;143(11):3562–3567. [PubMed] [Google Scholar]
- Widmer M. B., Morrissey P. J., Namen A. E., Voice R. F., Watson J. D. Interleukin 7 stimulates growth of fetal thymic precursors of cytolytic cells: induction of effector function by interleukin 2 and inhibition by interleukin 4. Int Immunol. 1990;2(11):1055–1061. doi: 10.1093/intimm/2.11.1055. [DOI] [PubMed] [Google Scholar]
- Zelenetz A. D., Chen T. T., Levy R. Histologic transformation of follicular lymphoma to diffuse lymphoma represents tumor progression by a single malignant B cell. J Exp Med. 1991 Jan 1;173(1):197–207. doi: 10.1084/jem.173.1.197. [DOI] [PMC free article] [PubMed] [Google Scholar]
