Skip to main content
NCBI home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1989 Mar 1;169(3):1101–1120. doi: 10.1084/jem.169.3.1101

Mature T-lineage leukemia with growth factor-induced multilineage differentiation

PMCID: PMC2189262  PMID: 2538542

Abstract

We report an acute T-lymphoblastic leukemia with a predominantly mature CD3+ CD7+ WT31+ phenotype that was induced to differentiate into different cell lineages by various recombinant human growth factors. In the presence of IL-3 or GM-CSF, the leukemic cells gave rise to myeloid and monocytic cells including terminally differentiated, partially functional, segmented neutrophilic granulocytes as assessed by morphologic, cytochemical, immunophenotypic, and functional criteria. In the presence of IL-2, leukemic granulated lymphoid cells exhibiting MHC-unrestricted cytotoxicity and expressing a CD2+ CD3+ CD5+ CD7+ CD8+ CD33+ WT31+ Leu19+ phenotype arose. Leukemic cell cultures initiated with IL-3 yielded growth factor-independent cells with a mixed lineage phenotype and morphologic and cytochemical evidence of immature blasts. These were T lymphocyte and myeloid surface antigen (CD2,CD3,CD5,CD7,CD13,CD33,WT31) positive. Identical rearrangements of the constant region of the TCR-delta gene and of the joining regions of the TCR-beta, -gamma, and -delta genes were observed in the fresh and all cultured leukemic cells, indicating that they were derived from the same malignant clone. Consistent with the molecular genetic data, the cytogenetic analyses of the GM-CSF-, IL-3-cultured and the growth factor-independent leukemic cells showed the presence of multiple, closely related abnormal clones, all of which had an interstitial deletion of part of the long arm of chromosome 6 and a complex 1;10;12 translocation. In conclusion, these data demonstrate the involvement of a multipotent leukemic precursor cell in this predominantly mature CD2+ CD3+ CD5+ CD7+ WT31+ T-ALL. This multipotent leukemic precursor may be susceptible to various growth factors and respond with ordered differentiation and maturation.

Full Text

The Full Text of this article is available as a PDF (1.4 MB).

Selected References

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

  1. Baer R., Boehm T., Yssel H., Spits H., Rabbitts T. H. Complex rearrangements within the human J delta-C delta/J alpha-C alpha locus and aberrant recombination between J alpha segments. EMBO J. 1988 Jun;7(6):1661–1668. doi: 10.1002/j.1460-2075.1988.tb02993.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Band H., Hochstenbach F., McLean J., Hata S., Krangel M. S., Brenner M. B. Immunochemical proof that a novel rearranging gene encodes the T cell receptor delta subunit. Science. 1987 Oct 30;238(4827):682–684. doi: 10.1126/science.3672118. [DOI] [PubMed] [Google Scholar]
  3. Begley C. G., Metcalf D., Nicola N. A. Purified colony stimulating factors (G-CSF and GM-CSF) induce differentiation in human HL60 leukemic cells with suppression of clonogenicity. Int J Cancer. 1987 Jan 15;39(1):99–105. doi: 10.1002/ijc.2910390118. [DOI] [PubMed] [Google Scholar]
  4. Breton-Gorius J., Reyes F., Vernant J. P., Tulliez M., Dreyfus B. The blast crisis of chronic granulocytic leukaemia: megakaryoblastic nature of cells as revealed by the presence of platelet-peroxidase--a cytochemical ultrastructural study. Br J Haematol. 1978 Jul;39(3):295–303. doi: 10.1111/j.1365-2141.1978.tb01101.x. [DOI] [PubMed] [Google Scholar]
  5. Broxmeyer H. E. Colony assays of hematopoietic progenitor cells and correlations to clinical situations. Crit Rev Oncol Hematol. 1984;1(3):227–257. doi: 10.1016/s1040-8428(84)80013-x. [DOI] [PubMed] [Google Scholar]
  6. Chien Y. H., Iwashima M., Kaplan K. B., Elliott J. F., Davis M. M. A new T-cell receptor gene located within the alpha locus and expressed early in T-cell differentiation. 1987 Jun 25-Jul 1Nature. 327(6124):677–682. doi: 10.1038/327677a0. [DOI] [PubMed] [Google Scholar]
  7. Chien Y. H., Iwashima M., Wettstein D. A., Kaplan K. B., Elliott J. F., Born W., Davis M. M. T-cell receptor delta gene rearrangements in early thymocytes. Nature. 1987 Dec 24;330(6150):722–727. doi: 10.1038/330722a0. [DOI] [PubMed] [Google Scholar]
  8. Clark S. C., Kamen R. The human hematopoietic colony-stimulating factors. Science. 1987 Jun 5;236(4806):1229–1237. doi: 10.1126/science.3296190. [DOI] [PubMed] [Google Scholar]
  9. Delwel R., Dorssers L., Touw I., Wagemaker G., Löwenberg B. Human recombinant multilineage colony stimulating factor (interleukin-3): stimulator of acute myelocytic leukemia progenitor cells in vitro. Blood. 1987 Jul;70(1):333–336. [PubMed] [Google Scholar]
  10. Dialynas D. P., Murre C., Quertermous T., Boss J. M., Leiden J. M., Seidman J. G., Strominger J. L. Cloning and sequence analysis of complementary DNA encoding an aberrantly rearranged human T-cell gamma chain. Proc Natl Acad Sci U S A. 1986 Apr;83(8):2619–2623. doi: 10.1073/pnas.83.8.2619. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Feinberg A. P., Vogelstein B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem. 1983 Jul 1;132(1):6–13. doi: 10.1016/0003-2697(83)90418-9. [DOI] [PubMed] [Google Scholar]
  12. Flynn P. J., Miller W. J., Weisdorf D. J., Arthur D. C., Brunning R., Branda R. F. Retinoic acid treatment of acute promyelocytic leukemia: in vitro and in vivo observations. Blood. 1983 Dec;62(6):1211–1217. [PubMed] [Google Scholar]
  13. Gasson J. C., Kaufman S. E., Weisbart R. H., Tomonaga M., Golde D. W. High-affinity binding of granulocyte-macrophage colony-stimulating factor to normal and leukemic human myeloid cells. Proc Natl Acad Sci U S A. 1986 Feb;83(3):669–673. doi: 10.1073/pnas.83.3.669. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Graham R. C., Jr, Karnovsky M. J. The early stages of absorption of injected horseradish peroxidase in the proximal tubules of mouse kidney: ultrastructural cytochemistry by a new technique. J Histochem Cytochem. 1966 Apr;14(4):291–302. doi: 10.1177/14.4.291. [DOI] [PubMed] [Google Scholar]
  15. Greaves M. F., Chan L. C., Furley A. J., Watt S. M., Molgaard H. V. Lineage promiscuity in hemopoietic differentiation and leukemia. Blood. 1986 Jan;67(1):1–11. [PubMed] [Google Scholar]
  16. Greenberg J. M., Kersey J. H. Terminal deoxynucleotidyl transferase expression can precede T cell receptor beta chain and gamma chain rearrangement in T cell acute lymphoblastic leukemia. Blood. 1987 Jan;69(1):356–360. [PubMed] [Google Scholar]
  17. Greenberg J. M., Quertermous T., Seidman J. G., Kersey J. H. Human T cell gamma-chain gene rearrangements in acute lymphoid and nonlymphoid leukemia: comparison with the T cell receptor beta-chain gene. J Immunol. 1986 Sep 15;137(6):2043–2049. [PubMed] [Google Scholar]
  18. Hata S., Brenner M. B., Krangel M. S. Identification of putative human T cell receptor delta complementary DNA clones. Science. 1987 Oct 30;238(4827):678–682. doi: 10.1126/science.3499667. [DOI] [PubMed] [Google Scholar]
  19. Hershfield M. S., Kurtzberg J., Harden E., Moore J. O., Whang-Peng J., Haynes B. F. Conversion of a stem cell leukemia from a T-lymphoid to a myeloid phenotype induced by the adenosine deaminase inhibitor 2'-deoxycoformycin. Proc Natl Acad Sci U S A. 1984 Jan;81(1):253–257. doi: 10.1073/pnas.81.1.253. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Hokland P., Hokland M., Daley J., Ritz J. Identification and cloning of a prethymic precursor T lymphocyte from a population of common acute lymphoblastic leukemia antigen (CALLA)-positive fetal bone marrow cells. J Exp Med. 1987 Jun 1;165(6):1749–1754. doi: 10.1084/jem.165.6.1749. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Jitsukawa S., Faure F., Lipinski M., Triebel F., Hercend T. A novel subset of human lymphocytes with a T cell receptor-gamma complex. J Exp Med. 1987 Oct 1;166(4):1192–1197. doi: 10.1084/jem.166.4.1192. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Kaufmann Y., Levanon M., Davidsohn J., Ramot B. Interleukin 2 induces human acute lymphocytic leukemia cells to manifest lymphokine-activated-killer (LAK) cytotoxicity. J Immunol. 1987 Aug 1;139(3):977–982. [PubMed] [Google Scholar]
  23. Kurtzberg J., Bigner S. H., Hershfield M. S. Establishment of the DU.528 human lymphohemopoietic stem cell line. J Exp Med. 1985 Nov 1;162(5):1561–1578. doi: 10.1084/jem.162.5.1561. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Lange B., Valtieri M., Santoli D., Caracciolo D., Mavilio F., Gemperlein I., Griffin C., Emanuel B., Finan J., Nowell P. Growth factor requirements of childhood acute leukemia: establishment of GM-CSF-dependent cell lines. Blood. 1987 Jul;70(1):192–199. [PubMed] [Google Scholar]
  25. Lanier L. L., Le A. M., Civin C. I., Loken M. R., Phillips J. H. The relationship of CD16 (Leu-11) and Leu-19 (NKH-1) antigen expression on human peripheral blood NK cells and cytotoxic T lymphocytes. J Immunol. 1986 Jun 15;136(12):4480–4486. [PubMed] [Google Scholar]
  26. Leary A. G., Yang Y. C., Clark S. C., Gasson J. C., Golde D. W., Ogawa M. Recombinant gibbon interleukin 3 supports formation of human multilineage colonies and blast cell colonies in culture: comparison with recombinant human granulocyte-macrophage colony-stimulating factor. Blood. 1987 Nov;70(5):1343–1348. [PubMed] [Google Scholar]
  27. Loh E. Y., Lanier L. L., Turck C. W., Littman D. R., Davis M. M., Chien Y. H., Weiss A. Identification and sequence of a fourth human T cell antigen receptor chain. Nature. 1987 Dec 10;330(6148):569–572. doi: 10.1038/330569a0. [DOI] [PubMed] [Google Scholar]
  28. Lopez A. F., To L. B., Yang Y. C., Gamble J. R., Shannon M. F., Burns G. F., Dyson P. G., Juttner C. A., Clark S., Vadas M. A. Stimulation of proliferation, differentiation, and function of human cells by primate interleukin 3. Proc Natl Acad Sci U S A. 1987 May;84(9):2761–2765. doi: 10.1073/pnas.84.9.2761. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Loughran T. P., Jr, Draves K. E., Starkebaum G., Kidd P., Clark E. A. Induction of NK activity in large granular lymphocyte leukemia: activation with anti-CD3 monoclonal antibody and interleukin 2. Blood. 1987 Jan;69(1):72–78. [PubMed] [Google Scholar]
  30. Messner H. A., Yamasaki K., Jamal N., Minden M. M., Yang Y. C., Wong G. G., Clark S. C. Growth of human hemopoietic colonies in response to recombinant gibbon interleukin 3: comparison with human recombinant granulocyte and granulocyte-macrophage colony-stimulating factor. Proc Natl Acad Sci U S A. 1987 Oct;84(19):6765–6769. doi: 10.1073/pnas.84.19.6765. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Miyauchi J., Kelleher C. A., Yang Y. C., Wong G. G., Clark S. C., Minden M. D., Minkin S., McCulloch E. A. The effects of three recombinant growth factors, IL-3, GM-CSF, and G-CSF, on the blast cells of acute myeloblastic leukemia maintained in short-term suspension culture. Blood. 1987 Sep;70(3):657–663. [PubMed] [Google Scholar]
  32. Morishima Y., Morishita Y., Adachi K., Tanimoto M., Ohno R., Saito H. Phorbol ester induces interleukin-2 receptor on the cell surface of precursor thymocyte leukemia with no rearrangement of T cell receptor beta and gamma genes. Blood. 1987 Nov;70(5):1291–1296. [PubMed] [Google Scholar]
  33. Nosaka T., Ohno H., Doi S., Fukuhara S., Miwa H., Kita K., Shirakawa S., Honjo T., Hatanaka M. Phenotypic conversion of T lymphoblastic lymphoma to acute biphenotypic leukemia composed of lymphoblasts and myeloblasts. Molecular genetic evidence of the same clonal origin. J Clin Invest. 1988 Jun;81(6):1824–1828. doi: 10.1172/JCI113526. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Ochoa A. C., Gromo G., Alter B. J., Sondel P. M., Bach F. H. Long-term growth of lymphokine-activated killer (LAK) cells: role of anti-CD3, beta-IL 1, interferon-gamma and -beta. J Immunol. 1987 Apr 15;138(8):2728–2733. [PubMed] [Google Scholar]
  35. Palacios R., Garland J. Distinct mechanisms may account for the growth-promoting activity of interleukin 3 on cells of lymphoid and myeloid origin. Proc Natl Acad Sci U S A. 1984 Feb;81(4):1208–1211. doi: 10.1073/pnas.81.4.1208. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Palacios R., Henson G., Steinmetz M., McKearn J. P. Interleukin-3 supports growth of mouse pre-B-cell clones in vitro. Nature. 1984 May 10;309(5964):126–131. doi: 10.1038/309126a0. [DOI] [PubMed] [Google Scholar]
  37. Ramsey K. M., Dyer D., Stocks N., Djeu J. Y. Enhancement of natural killer cell activity by interferon and interleukin-2 in human large granular lymphocytes inhibited by cyclosporine. Transplant Proc. 1984 Dec;16(6):1628–1631. [PubMed] [Google Scholar]
  38. Reinherz E. L., Kung P. C., Goldstein G., Levey R. H., Schlossman S. F. Discrete stages of human intrathymic differentiation: analysis of normal thymocytes and leukemic lymphoblasts of T-cell lineage. Proc Natl Acad Sci U S A. 1980 Mar;77(3):1588–1592. doi: 10.1073/pnas.77.3.1588. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Sanchez O., Escobar J. I., Yunis J. J. A simple G-banding technique. Lancet. 1973 Aug 4;2(7823):269–269. doi: 10.1016/s0140-6736(73)93180-2. [DOI] [PubMed] [Google Scholar]
  40. Sieff C. A., Niemeyer C. M., Nathan D. G., Ekern S. C., Bieber F. R., Yang Y. C., Wong G., Clark S. C. Stimulation of human hematopoietic colony formation by recombinant gibbon multi-colony-stimulating factor or interleukin 3. J Clin Invest. 1987 Sep;80(3):818–823. doi: 10.1172/JCI113139. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Smith L. J., Curtis J. E., Messner H. A., Senn J. S., Furthmayr H., McCulloch E. A. Lineage infidelity in acute leukemia. Blood. 1983 Jun;61(6):1138–1145. [PubMed] [Google Scholar]
  42. Sobol R. E., Mick R., Royston I., Davey F. R., Ellison R. R., Newman R., Cuttner J., Griffin J. D., Collins H., Nelson D. A. Clinical importance of myeloid antigen expression in adult acute lymphoblastic leukemia. N Engl J Med. 1987 Apr 30;316(18):1111–1117. doi: 10.1056/NEJM198704303161802. [DOI] [PubMed] [Google Scholar]
  43. Takihara Y., Tkachuk D., Michalopoulos E., Champagne E., Reimann J., Minden M., Mak T. W. Sequence and organization of the diversity, joining, and constant region genes of the human T-cell delta-chain locus. Proc Natl Acad Sci U S A. 1988 Aug;85(16):6097–6101. doi: 10.1073/pnas.85.16.6097. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Vellenga E., Ostapovicz D., O'Rourke B., Griffin J. D. Effects of recombinant IL-3, GM-CSF, and G-CSF on proliferation of leukemic clonogenic cells in short-term and long-term cultures. Leukemia. 1987 Aug;1(8):584–589. [PubMed] [Google Scholar]
  45. Whitlock C. A., Witte O. N. Long-term culture of B lymphocytes and their precursors from murine bone marrow. Proc Natl Acad Sci U S A. 1982 Jun;79(11):3608–3612. doi: 10.1073/pnas.79.11.3608. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Wong G. G., Witek J. S., Temple P. A., Wilkens K. M., Leary A. C., Luxenberg D. P., Jones S. S., Brown E. L., Kay R. M., Orr E. C. Human GM-CSF: molecular cloning of the complementary DNA and purification of the natural and recombinant proteins. Science. 1985 May 17;228(4701):810–815. doi: 10.1126/science.3923623. [DOI] [PubMed] [Google Scholar]
  47. Zarcone D., Prasthofer E. F., Malavasi F., Pistoia V., LoBuglio A. F., Grossi C. E. Ultrastructural analysis of human natural killer cell activation. Blood. 1987 Jun;69(6):1725–1736. [PubMed] [Google Scholar]
  48. Zipori D., Lee F. Introduction of interleukin-3 gene into stromal cells from the bone marrow alters hemopoietic differentiation but does not modify stem cell renewal. Blood. 1988 Mar;71(3):586–596. [PubMed] [Google Scholar]
  49. de Vries J. E., Vyth-Dreese F. A., Figdor C. G., Spits H., Leemans J. M., Bont W. S. Induction of phenotypic differentiation, interleukin 2 production, and PHA responsiveness of "immature" human thymocytes by interleukin 1 and phorbol ester. J Immunol. 1983 Jul;131(1):201–206. [PubMed] [Google Scholar]
  50. van de Griend R. J., Borst J., Tax W. J., Bolhuis R. L. Functional reactivity of WT31 monoclonal antibody with T cell receptor-gamma expressing CD3+4-8- T cells. J Immunol. 1988 Feb 15;140(4):1107–1110. [PubMed] [Google Scholar]
  51. van de Griend R. J., van Krimpen B. A., Ronteltap C. P., Bolhuis R. L. Rapidly expanded activated human killer cell clones have strong antitumor cell activity and have the surface phenotype of either T gamma, T-non-gamma, or null cells. J Immunol. 1984 Jun;132(6):3185–3191. [PubMed] [Google Scholar]

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

RESOURCES