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. 1996 Oct 1;15(19):5160–5166.

Tal-1 induces T cell acute lymphoblastic leukemia accelerated by casein kinase IIalpha.

M A Kelliher 1, D C Seldin 1, P Leder 1
PMCID: PMC452259  PMID: 8895560

Abstract

Ectopic activation of the TAL-1 gene in T lymphocytes occurs in the majority of cases of human T cell acute lymphoblastic leukemia (T-ALL), yet experiments to date have failed to demonstrate a direct transforming capability for tal-1. The tal-1 gene product is a serine phosphoprotein and basic helix-loop-helix (bHLH) transcription factor known to regulate embryonic hematopoiesis. We have established a transgenic mouse model in which tal-1 mis-expression in the thymus results in the development of clonal T cell lymphoblastic leukemia/lymphoma. Thus, overexpression of tal-1 alone can be transforming, verifying its pathogenic role in human T-ALL. In addition, leukemogenesis is accelerated dramatically by transgenic co-expression of tal-1 and the catalytic subunit of casein kinase IIalpha (CKIIalpha), a serine/threonine protein kinase known to modulate the activity of other bHLH transcription factors. Although tal-1 is a substrate for CKII, the synergy of the tal-1 and CKIIalpha transgenes appears to be indirect, perhaps mediated through the E protein heterodimeric partners of tal-1. These studies prove that dysregulated tal-1 is oncogenic, providing a direct molecular explanation for the malignancies associated with TAL-1 activation in human T-ALL.

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Selected References

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

  1. Abraham K. M., Levin S. D., Marth J. D., Forbush K. A., Perlmutter R. M. Thymic tumorigenesis induced by overexpression of p56lck. Proc Natl Acad Sci U S A. 1991 May 1;88(9):3977–3981. doi: 10.1073/pnas.88.9.3977. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Aplan P. D., Lombardi D. P., Ginsberg A. M., Cossman J., Bertness V. L., Kirsch I. R. Disruption of the human SCL locus by "illegitimate" V-(D)-J recombinase activity. Science. 1990 Dec 7;250(4986):1426–1429. doi: 10.1126/science.2255914. [DOI] [PubMed] [Google Scholar]
  3. Bash R. O., Hall S., Timmons C. F., Crist W. M., Amylon M., Smith R. G., Baer R. Does activation of the TAL1 gene occur in a majority of patients with T-cell acute lymphoblastic leukemia? A pediatric oncology group study. Blood. 1995 Jul 15;86(2):666–676. [PubMed] [Google Scholar]
  4. Begley C. G., Aplan P. D., Denning S. M., Haynes B. F., Waldmann T. A., Kirsch I. R. The gene SCL is expressed during early hematopoiesis and encodes a differentiation-related DNA-binding motif. Proc Natl Acad Sci U S A. 1989 Dec;86(24):10128–10132. doi: 10.1073/pnas.86.24.10128. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bernard O., Guglielmi P., Jonveaux P., Cherif D., Gisselbrecht S., Mauchauffe M., Berger R., Larsen C. J., Mathieu-Mahul D. Two distinct mechanisms for the SCL gene activation in the t(1;14) translocation of T-cell leukemias. Genes Chromosomes Cancer. 1990 Jan;1(3):194–208. doi: 10.1002/gcc.2870010303. [DOI] [PubMed] [Google Scholar]
  6. Brown L., Cheng J. T., Chen Q., Siciliano M. J., Crist W., Buchanan G., Baer R. Site-specific recombination of the tal-1 gene is a common occurrence in human T cell leukemia. EMBO J. 1990 Oct;9(10):3343–3351. doi: 10.1002/j.1460-2075.1990.tb07535.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Carroll A. J., Crist W. M., Link M. P., Amylon M. D., Pullen D. J., Ragab A. H., Buchanan G. R., Wimmer R. S., Vietti T. J. The t(1;14)(p34;q11) is nonrandom and restricted to T-cell acute lymphoblastic leukemia: a Pediatric Oncology Group study. Blood. 1990 Sep 15;76(6):1220–1224. [PubMed] [Google Scholar]
  8. Chen Q., Cheng J. T., Tasi L. H., Schneider N., Buchanan G., Carroll A., Crist W., Ozanne B., Siciliano M. J., Baer R. The tal gene undergoes chromosome translocation in T cell leukemia and potentially encodes a helix-loop-helix protein. EMBO J. 1990 Feb;9(2):415–424. doi: 10.1002/j.1460-2075.1990.tb08126.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Chen Q., Yang C. Y., Tsan J. T., Xia Y., Ragab A. H., Peiper S. C., Carroll A., Baer R. Coding sequences of the tal-1 gene are disrupted by chromosome translocation in human T cell leukemia. J Exp Med. 1990 Nov 1;172(5):1403–1408. doi: 10.1084/jem.172.5.1403. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Early P., Rogers J., Davis M., Calame K., Bond M., Wall R., Hood L. Two mRNAs can be produced from a single immunoglobulin mu gene by alternative RNA processing pathways. Cell. 1980 Jun;20(2):313–319. doi: 10.1016/0092-8674(80)90617-0. [DOI] [PubMed] [Google Scholar]
  11. Elwood N. J., Cook W. D., Metcalf D., Begley C. G. SCL, the gene implicated in human T-cell leukaemia, is oncogenic in a murine T-lymphocyte cell line. Oncogene. 1993 Nov;8(11):3093–3101. [PubMed] [Google Scholar]
  12. Finger L. R., Kagan J., Christopher G., Kurtzberg J., Hershfield M. S., Nowell P. C., Croce C. M. Involvement of the TCL5 gene on human chromosome 1 in T-cell leukemia and melanoma. Proc Natl Acad Sci U S A. 1989 Jul;86(13):5039–5043. doi: 10.1073/pnas.86.13.5039. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Garvin A. M., Abraham K. M., Forbush K. A., Farr A. G., Davison B. L., Perlmutter R. M. Disruption of thymocyte development and lymphomagenesis induced by SV40 T-antigen. Int Immunol. 1990;2(2):173–180. doi: 10.1093/intimm/2.2.173. [DOI] [PubMed] [Google Scholar]
  14. Goldfarb A. N., Goueli S., Mickelson D., Greenberg J. M. T-cell acute lymphoblastic leukemia--the associated gene SCL/tal codes for a 42-Kd nuclear phosphoprotein. Blood. 1992 Dec 1;80(11):2858–2866. [PubMed] [Google Scholar]
  15. Goldfarb A. N., Lewandowska K. Inhibition of cellular differentiation by the SCL/tal oncoprotein: transcriptional repression by an Id-like mechanism. Blood. 1995 Jan 15;85(2):465–471. [PubMed] [Google Scholar]
  16. Hsu H. L., Cheng J. T., Chen Q., Baer R. Enhancer-binding activity of the tal-1 oncoprotein in association with the E47/E12 helix-loop-helix proteins. Mol Cell Biol. 1991 Jun;11(6):3037–3042. doi: 10.1128/mcb.11.6.3037. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Hsu H. L., Wadman I., Baer R. Formation of in vivo complexes between the TAL1 and E2A polypeptides of leukemic T cells. Proc Natl Acad Sci U S A. 1994 Apr 12;91(8):3181–3185. doi: 10.1073/pnas.91.8.3181. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Hunter T., Karin M. The regulation of transcription by phosphorylation. Cell. 1992 Aug 7;70(3):375–387. doi: 10.1016/0092-8674(92)90162-6. [DOI] [PubMed] [Google Scholar]
  19. Johnson S. E., Wang X., Hardy S., Taparowsky E. J., Konieczny S. F. Casein kinase II increases the transcriptional activities of MRF4 and MyoD independently of their direct phosphorylation. Mol Cell Biol. 1996 Apr;16(4):1604–1613. doi: 10.1128/mcb.16.4.1604. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Krane I. M., Leder P. NDF/heregulin induces persistence of terminal end buds and adenocarcinomas in the mammary glands of transgenic mice. Oncogene. 1996 Apr 18;12(8):1781–1788. [PubMed] [Google Scholar]
  21. Krieg P. A., Melton D. A. In vitro RNA synthesis with SP6 RNA polymerase. Methods Enzymol. 1987;155:397–415. doi: 10.1016/0076-6879(87)55027-3. [DOI] [PubMed] [Google Scholar]
  22. Larson R. C., Lavenir I., Larson T. A., Baer R., Warren A. J., Wadman I., Nottage K., Rabbitts T. H. Protein dimerization between Lmo2 (Rbtn2) and Tal1 alters thymocyte development and potentiates T cell tumorigenesis in transgenic mice. EMBO J. 1996 Mar 1;15(5):1021–1027. [PMC free article] [PubMed] [Google Scholar]
  23. McGuire E. A., Rintoul C. E., Sclar G. M., Korsmeyer S. J. Thymic overexpression of Ttg-1 in transgenic mice results in T-cell acute lymphoblastic leukemia/lymphoma. Mol Cell Biol. 1992 Sep;12(9):4186–4196. doi: 10.1128/mcb.12.9.4186. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Porcher C., Swat W., Rockwell K., Fujiwara Y., Alt F. W., Orkin S. H. The T cell leukemia oncoprotein SCL/tal-1 is essential for development of all hematopoietic lineages. Cell. 1996 Jul 12;86(1):47–57. doi: 10.1016/s0092-8674(00)80076-8. [DOI] [PubMed] [Google Scholar]
  25. Portoles P., Rojo J., Golby A., Bonneville M., Gromkowski S., Greenbaum L., Janeway C. A., Jr, Murphy D. B., Bottomly K. Monoclonal antibodies to murine CD3 epsilon define distinct epitopes, one of which may interact with CD4 during T cell activation. J Immunol. 1989 Jun 15;142(12):4169–4175. [PubMed] [Google Scholar]
  26. Robb L., Rasko J. E., Bath M. L., Strasser A., Begley C. G. scl, a gene frequently activated in human T cell leukaemia, does not induce lymphomas in transgenic mice. Oncogene. 1995 Jan 5;10(1):205–209. [PubMed] [Google Scholar]
  27. Samelson L. E., O'Shea J. J., Luong H., Ross P., Urdahl K. B., Klausner R. D., Bluestone J. T cell antigen receptor phosphorylation induced by an anti-receptor antibody. J Immunol. 1987 Oct 15;139(8):2708–2714. [PubMed] [Google Scholar]
  28. Seldin D. C., Leder P. Casein kinase II alpha transgene-induced murine lymphoma: relation to theileriosis in cattle. Science. 1995 Feb 10;267(5199):894–897. doi: 10.1126/science.7846532. [DOI] [PubMed] [Google Scholar]
  29. Sentman C. L., Shutter J. R., Hockenbery D., Kanagawa O., Korsmeyer S. J. bcl-2 inhibits multiple forms of apoptosis but not negative selection in thymocytes. Cell. 1991 Nov 29;67(5):879–888. doi: 10.1016/0092-8674(91)90361-2. [DOI] [PubMed] [Google Scholar]
  30. Shivdasani R. A., Mayer E. L., Orkin S. H. Absence of blood formation in mice lacking the T-cell leukaemia oncoprotein tal-1/SCL. Nature. 1995 Feb 2;373(6513):432–434. doi: 10.1038/373432a0. [DOI] [PubMed] [Google Scholar]
  31. Siu G., Clark S. P., Yoshikai Y., Malissen M., Yanagi Y., Strauss E., Mak T. W., Hood L. The human T cell antigen receptor is encoded by variable, diversity, and joining gene segments that rearrange to generate a complete V gene. Cell. 1984 Jun;37(2):393–401. doi: 10.1016/0092-8674(84)90369-6. [DOI] [PubMed] [Google Scholar]
  32. Taketo M., Schroeder A. C., Mobraaten L. E., Gunning K. B., Hanten G., Fox R. R., Roderick T. H., Stewart C. L., Lilly F., Hansen C. T. FVB/N: an inbred mouse strain preferable for transgenic analyses. Proc Natl Acad Sci U S A. 1991 Mar 15;88(6):2065–2069. doi: 10.1073/pnas.88.6.2065. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Valge-Archer V. E., Osada H., Warren A. J., Forster A., Li J., Baer R., Rabbitts T. H. The LIM protein RBTN2 and the basic helix-loop-helix protein TAL1 are present in a complex in erythroid cells. Proc Natl Acad Sci U S A. 1994 Aug 30;91(18):8617–8621. doi: 10.1073/pnas.91.18.8617. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Voronova A. F., Lee F. The E2A and tal-1 helix-loop-helix proteins associate in vivo and are modulated by Id proteins during interleukin 6-induced myeloid differentiation. Proc Natl Acad Sci U S A. 1994 Jun 21;91(13):5952–5956. doi: 10.1073/pnas.91.13.5952. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Warren A. J., Colledge W. H., Carlton M. B., Evans M. J., Smith A. J., Rabbitts T. H. The oncogenic cysteine-rich LIM domain protein rbtn2 is essential for erythroid development. Cell. 1994 Jul 15;78(1):45–57. doi: 10.1016/0092-8674(94)90571-1. [DOI] [PubMed] [Google Scholar]
  36. Wildin R. S., Garvin A. M., Pawar S., Lewis D. B., Abraham K. M., Forbush K. A., Ziegler S. F., Allen J. M., Perlmutter R. M. Developmental regulation of lck gene expression in T lymphocytes. J Exp Med. 1991 Feb 1;173(2):383–393. doi: 10.1084/jem.173.2.383. [DOI] [PMC free article] [PubMed] [Google Scholar]

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