Skip to main content
PMC home page
Molecular and Cellular Biology logoLink to Molecular and Cellular Biology
. 1996 Aug;16(8):4107–4116. doi: 10.1128/mcb.16.8.4107

Oligomerization of the ABL tyrosine kinase by the Ets protein TEL in human leukemia.

T R Golub 1, A Goga 1, G F Barker 1, D E Afar 1, J McLaughlin 1, S K Bohlander 1, J D Rowley 1, O N Witte 1, D G Gilliland 1
PMCID: PMC231407  PMID: 8754809

Abstract

TEL is a member of the Ets family of transcription factors which are frequently rearranged in human leukemia. The mechanism of TEL-mediated transformation, however, is unknown. We report the cloning and characterization of a chromosomal translocation associated with acute myeloid leukemia which fuses TEL to the ABL tyrosine kinase. The TEL-ABL fusion confers growth factor-independent growth to the marine hematopoietic cell line Ba/F3 and transforms Rat-1 fibroblasts and primary murine bone marrow cells. TEL-ABL is constitutively tyrosine phosphorylated and localizes to the cytoskeleton. A TEL-ABL mutant containing an ABL kinase-inactivating mutation is not constitutively phosphorylated and is nontransforming but retains cytoskeletal localization. However, constitutive phosphorylation, cytoskeletal localization, and transformation are all dependent upon a highly conserved region of TEL termed the helix-loop-helix (HLH) domain. TEL-ABL formed HLH-dependent homo-oligomers in vitro, a process critical for tyrosine kinase activation. These experiments suggest that oligomerization of TEL-ABL mediated by the TEL HLH domain is required for tyrosine kinase activation, cytoskeletal localization, and transformation. These data also suggest that oligomerization of Ets proteins through the highly conserved HLH domain may represent a previously unrecognized phenomenon.

Full Text

The Full Text of this article is available as a PDF (652.6 KB).

Selected References

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

  1. Afar D. E., Goga A., McLaughlin J., Witte O. N., Sawyers C. L. Differential complementation of Bcr-Abl point mutants with c-Myc. Science. 1994 Apr 15;264(5157):424–426. doi: 10.1126/science.8153630. [DOI] [PubMed] [Google Scholar]
  2. Barker G. F., Beemon K. Nonsense codons within the Rous sarcoma virus gag gene decrease the stability of unspliced viral RNA. Mol Cell Biol. 1991 May;11(5):2760–2768. doi: 10.1128/mcb.11.5.2760. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Ben-David Y., Giddens E. B., Letwin K., Bernstein A. Erythroleukemia induction by Friend murine leukemia virus: insertional activation of a new member of the ets gene family, Fli-1, closely linked to c-ets-1. Genes Dev. 1991 Jun;5(6):908–918. doi: 10.1101/gad.5.6.908. [DOI] [PubMed] [Google Scholar]
  4. Birren B. W., Lai E., Hood L., Simon M. I. Pulsed field gel electrophoresis techniques for separating 1- to 50-kilobase DNA fragments. Anal Biochem. 1989 Mar;177(2):282–286. doi: 10.1016/0003-2697(89)90052-3. [DOI] [PubMed] [Google Scholar]
  5. Bongarzone I., Monzini N., Borrello M. G., Carcano C., Ferraresi G., Arighi E., Mondellini P., Della Porta G., Pierotti M. A. Molecular characterization of a thyroid tumor-specific transforming sequence formed by the fusion of ret tyrosine kinase and the regulatory subunit RI alpha of cyclic AMP-dependent protein kinase A. Mol Cell Biol. 1993 Jan;13(1):358–366. doi: 10.1128/mcb.13.1.358. [DOI] [PMC free article] [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. Corral J., Forster A., Thompson S., Lampert F., Kaneko Y., Slater R., Kroes W. G., van der Schoot C. E., Ludwig W. D., Karpas A. Acute leukemias of different lineages have similar MLL gene fusions encoding related chimeric proteins resulting from chromosomal translocation. Proc Natl Acad Sci U S A. 1993 Sep 15;90(18):8538–8542. doi: 10.1073/pnas.90.18.8538. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Croce C. M., Nowell P. C. Molecular basis of human B cell neoplasia. Blood. 1985 Jan;65(1):1–7. [PubMed] [Google Scholar]
  9. Delattre O., Zucman J., Plougastel B., Desmaze C., Melot T., Peter M., Kovar H., Joubert I., de Jong P., Rouleau G. Gene fusion with an ETS DNA-binding domain caused by chromosome translocation in human tumours. Nature. 1992 Sep 10;359(6391):162–165. doi: 10.1038/359162a0. [DOI] [PubMed] [Google Scholar]
  10. Ellis C., Moran M., McCormick F., Pawson T. Phosphorylation of GAP and GAP-associated proteins by transforming and mitogenic tyrosine kinases. Nature. 1990 Jan 25;343(6256):377–381. doi: 10.1038/343377a0. [DOI] [PubMed] [Google Scholar]
  11. Erickson P., Gao J., Chang K. S., Look T., Whisenant E., Raimondi S., Lasher R., Trujillo J., Rowley J., Drabkin H. Identification of breakpoints in t(8;21) acute myelogenous leukemia and isolation of a fusion transcript, AML1/ETO, with similarity to Drosophila segmentation gene, runt. Blood. 1992 Oct 1;80(7):1825–1831. [PubMed] [Google Scholar]
  12. Frohman M. A. Rapid amplification of complementary DNA ends for generation of full-length complementary DNAs: thermal RACE. Methods Enzymol. 1993;218:340–356. doi: 10.1016/0076-6879(93)18026-9. [DOI] [PubMed] [Google Scholar]
  13. Goga A., McLaughlin J., Afar D. E., Saffran D. C., Witte O. N. Alternative signals to RAS for hematopoietic transformation by the BCR-ABL oncogene. Cell. 1995 Sep 22;82(6):981–988. doi: 10.1016/0092-8674(95)90277-5. [DOI] [PubMed] [Google Scholar]
  14. Goga A., McLaughlin J., Pendergast A. M., Parmar K., Muller A., Rosenberg N., Witte O. N. Oncogenic activation of c-ABL by mutation within its last exon. Mol Cell Biol. 1993 Aug;13(8):4967–4975. doi: 10.1128/mcb.13.8.4967. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Golub T. R., Barker G. F., Bohlander S. K., Hiebert S. W., Ward D. C., Bray-Ward P., Morgan E., Raimondi S. C., Rowley J. D., Gilliland D. G. Fusion of the TEL gene on 12p13 to the AML1 gene on 21q22 in acute lymphoblastic leukemia. Proc Natl Acad Sci U S A. 1995 May 23;92(11):4917–4921. doi: 10.1073/pnas.92.11.4917. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Golub T. R., Barker G. F., Lovett M., Gilliland D. G. Fusion of PDGF receptor beta to a novel ets-like gene, tel, in chronic myelomonocytic leukemia with t(5;12) chromosomal translocation. Cell. 1994 Apr 22;77(2):307–316. doi: 10.1016/0092-8674(94)90322-0. [DOI] [PubMed] [Google Scholar]
  17. Hajra A., Liu P. P., Speck N. A., Collins F. S. Overexpression of core-binding factor alpha (CBF alpha) reverses cellular transformation by the CBF beta-smooth muscle myosin heavy chain chimeric oncoprotein. Mol Cell Biol. 1995 Sep;15(9):4980–4989. doi: 10.1128/mcb.15.9.4980. [DOI] [PMC free article] [PubMed] [Google Scholar] [Retracted]
  18. Heldin C. H., Ernlund A., Rorsman C., Rönnstrand L. Dimerization of B-type platelet-derived growth factor receptors occurs after ligand binding and is closely associated with receptor kinase activation. J Biol Chem. 1989 May 25;264(15):8905–8912. [PubMed] [Google Scholar]
  19. Jeon I. S., Davis J. N., Braun B. S., Sublett J. E., Roussel M. F., Denny C. T., Shapiro D. N. A variant Ewing's sarcoma translocation (7;22) fuses the EWS gene to the ETS gene ETV1. Oncogene. 1995 Mar 16;10(6):1229–1234. [PubMed] [Google Scholar]
  20. Klämbt C. The Drosophila gene pointed encodes two ETS-like proteins which are involved in the development of the midline glial cells. Development. 1993 Jan;117(1):163–176. doi: 10.1242/dev.117.1.163. [DOI] [PubMed] [Google Scholar]
  21. Kobayashi H., Montgomery K. T., Bohlander S. K., Adra C. N., Lim B. L., Kucherlapati R. S., Donis-Keller H., Holt M. S., Le Beau M. M., Rowley J. D. Fluorescence in situ hybridization mapping of translocations and deletions involving the short arm of human chromosome 12 in malignant hematologic diseases. Blood. 1994 Nov 15;84(10):3473–3482. [PubMed] [Google Scholar]
  22. Liu P., Tarlé S. A., Hajra A., Claxton D. F., Marlton P., Freedman M., Siciliano M. J., Collins F. S. Fusion between transcription factor CBF beta/PEBP2 beta and a myosin heavy chain in acute myeloid leukemia. Science. 1993 Aug 20;261(5124):1041–1044. doi: 10.1126/science.8351518. [DOI] [PubMed] [Google Scholar]
  23. Lugo T. G., Pendergast A. M., Muller A. J., Witte O. N. Tyrosine kinase activity and transformation potency of bcr-abl oncogene products. Science. 1990 Mar 2;247(4946):1079–1082. doi: 10.1126/science.2408149. [DOI] [PubMed] [Google Scholar]
  24. McLaughlin J., Chianese E., Witte O. N. In vitro transformation of immature hematopoietic cells by the P210 BCR/ABL oncogene product of the Philadelphia chromosome. Proc Natl Acad Sci U S A. 1987 Sep;84(18):6558–6562. doi: 10.1073/pnas.84.18.6558. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. McWhirter J. R., Galasso D. L., Wang J. Y. A coiled-coil oligomerization domain of Bcr is essential for the transforming function of Bcr-Abl oncoproteins. Mol Cell Biol. 1993 Dec;13(12):7587–7595. doi: 10.1128/mcb.13.12.7587. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. McWhirter J. R., Wang J. Y. An actin-binding function contributes to transformation by the Bcr-Abl oncoprotein of Philadelphia chromosome-positive human leukemias. EMBO J. 1993 Apr;12(4):1533–1546. doi: 10.1002/j.1460-2075.1993.tb05797.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Meyers S., Lenny N., Hiebert S. W. The t(8;21) fusion protein interferes with AML-1B-dependent transcriptional activation. Mol Cell Biol. 1995 Apr;15(4):1974–1982. doi: 10.1128/mcb.15.4.1974. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Miyoshi H., Shimizu K., Kozu T., Maseki N., Kaneko Y., Ohki M. t(8;21) breakpoints on chromosome 21 in acute myeloid leukemia are clustered within a limited region of a single gene, AML1. Proc Natl Acad Sci U S A. 1991 Dec 1;88(23):10431–10434. doi: 10.1073/pnas.88.23.10431. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Moreau-Gachelin F., Ray D., Mattei M. G., Tambourin P., Tavitian A. The putative oncogene Spi-1: murine chromosomal localization and transcriptional activation in murine acute erythroleukemias. Oncogene. 1989 Dec;4(12):1449–1456. [PubMed] [Google Scholar]
  30. Muller A. J., Young J. C., Pendergast A. M., Pondel M., Landau N. R., Littman D. R., Witte O. N. BCR first exon sequences specifically activate the BCR/ABL tyrosine kinase oncogene of Philadelphia chromosome-positive human leukemias. Mol Cell Biol. 1991 Apr;11(4):1785–1792. doi: 10.1128/mcb.11.4.1785. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Nisson P. E., Watkins P. C., Sacchi N. Transcriptionally active chimeric gene derived from the fusion of the AML1 gene and a novel gene on chromosome 8 in t(8;21) leukemic cells. Cancer Genet Cytogenet. 1992 Oct 15;63(2):81–88. doi: 10.1016/0165-4608(92)90384-k. [DOI] [PubMed] [Google Scholar]
  32. O'Neill E. M., Rebay I., Tjian R., Rubin G. M. The activities of two Ets-related transcription factors required for Drosophila eye development are modulated by the Ras/MAPK pathway. Cell. 1994 Jul 15;78(1):137–147. doi: 10.1016/0092-8674(94)90580-0. [DOI] [PubMed] [Google Scholar]
  33. Papadopoulos P., Ridge S. A., Boucher C. A., Stocking C., Wiedemann L. M. The novel activation of ABL by fusion to an ets-related gene, TEL. Cancer Res. 1995 Jan 1;55(1):34–38. [PubMed] [Google Scholar]
  34. Pear W. S., Nolan G. P., Scott M. L., Baltimore D. Production of high-titer helper-free retroviruses by transient transfection. Proc Natl Acad Sci U S A. 1993 Sep 15;90(18):8392–8396. doi: 10.1073/pnas.90.18.8392. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Pendergast A. M., Gishizky M. L., Havlik M. H., Witte O. N. SH1 domain autophosphorylation of P210 BCR/ABL is required for transformation but not growth factor independence. Mol Cell Biol. 1993 Mar;13(3):1728–1736. doi: 10.1128/mcb.13.3.1728. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Prywes R., Foulkes J. G., Baltimore D. The minimum transforming region of v-abl is the segment encoding protein-tyrosine kinase. J Virol. 1985 Apr;54(1):114–122. doi: 10.1128/jvi.54.1.114-122.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Rao V. N., Ohno T., Prasad D. D., Bhattacharya G., Reddy E. S. Analysis of the DNA-binding and transcriptional activation functions of human Fli-1 protein. Oncogene. 1993 Aug;8(8):2167–2173. [PubMed] [Google Scholar]
  38. Rodrigues G. A., Park M. Dimerization mediated through a leucine zipper activates the oncogenic potential of the met receptor tyrosine kinase. Mol Cell Biol. 1993 Nov;13(11):6711–6722. doi: 10.1128/mcb.13.11.6711. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Romana S. P., Mauchauffé M., Le Coniat M., Chumakov I., Le Paslier D., Berger R., Bernard O. A. The t(12;21) of acute lymphoblastic leukemia results in a tel-AML1 gene fusion. Blood. 1995 Jun 15;85(12):3662–3670. [PubMed] [Google Scholar]
  40. Rowley J. D. Letter: A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature. 1973 Jun 1;243(5405):290–293. doi: 10.1038/243290a0. [DOI] [PubMed] [Google Scholar]
  41. Salgia R., Li J. L., Lo S. H., Brunkhorst B., Kansas G. S., Sobhany E. S., Sun Y., Pisick E., Hallek M., Ernst T. Molecular cloning of human paxillin, a focal adhesion protein phosphorylated by P210BCR/ABL. J Biol Chem. 1995 Mar 10;270(10):5039–5047. doi: 10.1074/jbc.270.10.5039. [DOI] [PubMed] [Google Scholar]
  42. Seth A., Papas T. S. The c-ets-1 proto-oncogene has oncogenic activity and is positively autoregulated. Oncogene. 1990 Dec;5(12):1761–1767. [PubMed] [Google Scholar]
  43. Shimizu K., Ichikawa H., Tojo A., Kaneko Y., Maseki N., Hayashi Y., Ohira M., Asano S., Ohki M. An ets-related gene, ERG, is rearranged in human myeloid leukemia with t(16;21) chromosomal translocation. Proc Natl Acad Sci U S A. 1993 Nov 1;90(21):10280–10284. doi: 10.1073/pnas.90.21.10280. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Shtivelman E., Lifshitz B., Gale R. P., Canaani E. Fused transcript of abl and bcr genes in chronic myelogenous leukaemia. Nature. 1985 Jun 13;315(6020):550–554. doi: 10.1038/315550a0. [DOI] [PubMed] [Google Scholar]
  45. Sorensen P. H., Lessnick S. L., Lopez-Terrada D., Liu X. F., Triche T. J., Denny C. T. A second Ewing's sarcoma translocation, t(21;22), fuses the EWS gene to another ETS-family transcription factor, ERG. Nat Genet. 1994 Feb;6(2):146–151. doi: 10.1038/ng0294-146. [DOI] [PubMed] [Google Scholar]
  46. Van Etten R. A., Jackson P. K., Baltimore D., Sanders M. C., Matsudaira P. T., Janmey P. A. The COOH terminus of the c-Abl tyrosine kinase contains distinct F- and G-actin binding domains with bundling activity. J Cell Biol. 1994 Feb;124(3):325–340. doi: 10.1083/jcb.124.3.325. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Wasylyk B., Hahn S. L., Giovane A. The Ets family of transcription factors. Eur J Biochem. 1993 Jan 15;211(1-2):7–18. doi: 10.1007/978-3-642-78757-7_2. [DOI] [PubMed] [Google Scholar]
  48. Wisniewski D., Strife A., Wojciechowicz D., Lambek C., Clarkson B. A 62-kilodalton tyrosine phosphoprotein constitutively present in primary chronic phase chronic myelogenous leukemia enriched lineage negative blast populations. Leukemia. 1994 Apr;8(4):688–693. [PubMed] [Google Scholar]
  49. Wong G., Müller O., Clark R., Conroy L., Moran M. F., Polakis P., McCormick F. Molecular cloning and nucleic acid binding properties of the GAP-associated tyrosine phosphoprotein p62. Cell. 1992 May 1;69(3):551–558. doi: 10.1016/0092-8674(92)90455-l. [DOI] [PubMed] [Google Scholar]

Articles from Molecular and Cellular Biology are provided here courtesy of Taylor & Francis

RESOURCES