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Mol Cell Biol. 1991 April; 11(4): 1785–1792.
PMCID: PMC359845

BCR first exon sequences specifically activate the BCR/ABL tyrosine kinase oncogene of Philadelphia chromosome-positive human leukemias.

Abstract

The c-abl proto-oncogene encodes a cytoplasmic tyrosine kinase which is homologous to the src gene product in its kinase domain and in the upstream kinase regulatory domains SH2 (src homology region 2) and SH3 (src homology region 3). The murine v-abl oncogene product has lost the SH3 domain as a consequence of N-terminal fusion of gag sequences. Deletion of the SH3 domain is sufficient to render the murine c-abl proto-oncogene product transforming when myristylated N-terminal membrane localization sequences are also present. In contrast, the human BCR/ABL oncogene of the Philadelphia chromosome translocation has an intact SH3 domain and its product is not myristylated at the N terminus. To analyze the contribution of BCR-encoded sequences to BCR/ABL-mediated transformation, the effects of a series of deletions and substitutions were assessed in fibroblast and hematopoietic-cell transformation assays. BCR first-exon sequences specifically potentiate transformation and tyrosine kinase activation when they are fused to the second exon of otherwise intact c-ABL. This suggests that BCR-encoded sequences specifically interfere with negative regulation of the ABL-encoded tyrosine kinase, which would represent a novel mechanism for the activation of nonreceptor tyrosine kinase-encoding proto-oncogenes.

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Selected References

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  • Ben-Neriah Y, Bernards A, Paskind M, Daley GQ, Baltimore D. Alternative 5' exons in c-abl mRNA. Cell. 1986 Feb 28;44(4):577–586. [PubMed]
  • Bergold PJ, Blumenthal JA, D'Andrea E, Snyder HW, Lederman L, Silverstone A, Nguyen H, Besmer P. Nucleic acid sequence and oncogenic properties of the HZ2 feline sarcoma virus v-abl insert. J Virol. 1987 Apr;61(4):1193–1202. [PMC free article] [PubMed]
  • Chen SJ, Chen Z, Grausz JD, Hillion J, d'Auriol L, Flandrin G, Larsen CJ, Berger R. Molecular cloning of a 5' segment of the genomic phl gene defines a new breakpoint cluster region (bcr2) in Philadelphia-positive acute leukemias. Leukemia. 1988 Oct;2(10):634–641. [PubMed]
  • Clark SS, Crist WM, Witte ON. Molecular pathogenesis of Ph-positive leukemias. Annu Rev Med. 1989;40:113–122. [PubMed]
  • Coulier F, Martin-Zanca D, Ernst M, Barbacid M. Mechanism of activation of the human trk oncogene. Mol Cell Biol. 1989 Jan;9(1):15–23. [PMC free article] [PubMed]
  • Daley GQ, McLaughlin J, Witte ON, Baltimore D. The CML-specific P210 bcr/abl protein, unlike v-abl, does not transform NIH/3T3 fibroblasts. Science. 1987 Jul 31;237(4814):532–535. [PubMed]
  • Daley GQ, Van Etten RA, Baltimore D. Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. Science. 1990 Feb 16;247(4944):824–830. [PubMed]
  • Denny CT, Shah NP, Ogden S, Willman C, McConnell T, Crist W, Carroll A, Witte ON. Localization of preferential sites of rearrangement within the BCR gene in Philadelphia chromosome-positive acute lymphoblastic leukemia. Proc Natl Acad Sci U S A. 1989 Jun;86(11):4254–4258. [PubMed]
  • Downward J, Riehl R, Wu L, Weinberg RA. Identification of a nucleotide exchange-promoting activity for p21ras. Proc Natl Acad Sci U S A. 1990 Aug;87(15):5998–6002. [PubMed]
  • Elefanty AG, Hariharan IK, Cory S. bcr-abl, the hallmark of chronic myeloid leukaemia in man, induces multiple haemopoietic neoplasms in mice. EMBO J. 1990 Apr;9(4):1069–1078. [PubMed]
  • 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. [PubMed]
  • Fainstein E, Einat M, Gokkel E, Marcelle C, Croce CM, Gale RP, Canaani E. Nucleotide sequence analysis of human abl and bcr-abl cDNAs. Oncogene. 1989 Dec;4(12):1477–1481. [PubMed]
  • Franz WM, Berger P, Wang JY. Deletion of an N-terminal regulatory domain of the c-abl tyrosine kinase activates its oncogenic potential. EMBO J. 1989 Jan;8(1):137–147. [PubMed]
  • Groffen J, Stephenson JR, Heisterkamp N, de Klein A, Bartram CR, Grosveld G. Philadelphia chromosomal breakpoints are clustered within a limited region, bcr, on chromosome 22. Cell. 1984 Jan;36(1):93–99. [PubMed]
  • Hall CV, Jacob PE, Ringold GM, Lee F. Expression and regulation of Escherichia coli lacZ gene fusions in mammalian cells. J Mol Appl Genet. 1983;2(1):101–109. [PubMed]
  • Hamaguchi M, Grandori C, Hanafusa H. Phosphorylation of cellular proteins in Rous sarcoma virus-infected cells: analysis by use of anti-phosphotyrosine antibodies. Mol Cell Biol. 1988 Aug;8(8):3035–3042. [PMC free article] [PubMed]
  • Hanks SK, Quinn AM, Hunter T. The protein kinase family: conserved features and deduced phylogeny of the catalytic domains. Science. 1988 Jul 1;241(4861):42–52. [PubMed]
  • Heisterkamp N, Jenster G, ten Hoeve J, Zovich D, Pattengale PK, Groffen J. Acute leukaemia in bcr/abl transgenic mice. Nature. 1990 Mar 15;344(6263):251–253. [PubMed]
  • Hirai H, Varmus HE. Site-directed mutagenesis of the SH2- and SH3-coding domains of c-src produces varied phenotypes, including oncogenic activation of p60c-src. Mol Cell Biol. 1990 Apr;10(4):1307–1318. [PMC free article] [PubMed]
  • Hunter T. A tail of two src's: mutatis mutandis. Cell. 1987 Apr 10;49(1):1–4. [PubMed]
  • Jackson P, Baltimore D. N-terminal mutations activate the leukemogenic potential of the myristoylated form of c-abl. EMBO J. 1989 Feb;8(2):449–456. [PubMed]
  • Kato JY, Takeya T, Grandori C, Iba H, Levy JB, Hanafusa H. Amino acid substitutions sufficient to convert the nontransforming p60c-src protein to a transforming protein. Mol Cell Biol. 1986 Dec;6(12):4155–4160. [PMC free article] [PubMed]
  • Kelliher MA, McLaughlin J, Witte ON, Rosenberg N. Induction of a chronic myelogenous leukemia-like syndrome in mice with v-abl and BCR/ABL. Proc Natl Acad Sci U S A. 1990 Sep;87(17):6649–6653. [PubMed]
  • Kirschmeier PT, Housey GM, Johnson MD, Perkins AS, Weinstein IB. Construction and characterization of a retroviral vector demonstrating efficient expression of cloned cDNA sequences. DNA. 1988 Apr;7(3):219–225. [PubMed]
  • Konopka JB, Witte ON. Detection of c-abl tyrosine kinase activity in vitro permits direct comparison of normal and altered abl gene products. Mol Cell Biol. 1985 Nov;5(11):3116–3123. [PMC free article] [PubMed]
  • Lebkowski JS, DuBridge RB, Antell EA, Greisen KS, Calos MP. Transfected DNA is mutated in monkey, mouse, and human cells. Mol Cell Biol. 1984 Oct;4(10):1951–1960. [PMC free article] [PubMed]
  • Lifshitz B, Fainstein E, Marcelle C, Shtivelman E, Amson R, Gale RP, Canaani E. bcr genes and transcripts. Oncogene. 1988 Feb;2(2):113–117. [PubMed]
  • LOWRY OH, ROSEBROUGH NJ, FARR AL, RANDALL RJ. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed]
  • Lugo TG, Pendergast AM, Muller AJ, Witte ON. Tyrosine kinase activity and transformation potency of bcr-abl oncogene products. Science. 1990 Mar 2;247(4946):1079–1082. [PubMed]
  • Lugo TG, Witte ON. The BCR-ABL oncogene transforms Rat-1 cells and cooperates with v-myc. Mol Cell Biol. 1989 Mar;9(3):1263–1270. [PMC free article] [PubMed]
  • Martin-Zanca D, Hughes SH, Barbacid M. A human oncogene formed by the fusion of truncated tropomyosin and protein tyrosine kinase sequences. Nature. 319(6056):743–748. [PubMed]
  • Mayer BJ, Hamaguchi M, Hanafusa H. A novel viral oncogene with structural similarity to phospholipase C. Nature. 1988 Mar 17;332(6161):272–275. [PubMed]
  • McLaughlin J, Chianese E, Witte ON. 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. [PubMed]
  • McLaughlin J, Chianese E, Witte ON. Alternative forms of the BCR-ABL oncogene have quantitatively different potencies for stimulation of immature lymphoid cells. Mol Cell Biol. 1989 May;9(5):1866–1874. [PMC free article] [PubMed]
  • Mes-Masson AM, McLaughlin J, Daley GQ, Paskind M, Witte ON. Overlapping cDNA clones define the complete coding region for the P210c-abl gene product associated with chronic myelogenous leukemia cells containing the Philadelphia chromosome. Proc Natl Acad Sci U S A. 1986 Dec;83(24):9768–9772. [PubMed]
  • O'Brien MC, Fukui Y, Hanafusa H. Activation of the proto-oncogene p60c-src by point mutations in the SH2 domain. Mol Cell Biol. 1990 Jun;10(6):2855–2862. [PMC free article] [PubMed]
  • Pawson T. Non-catalytic domains of cytoplasmic protein-tyrosine kinases: regulatory elements in signal transduction. Oncogene. 1988 Nov;3(5):491–495. [PubMed]
  • Potts WM, Reynolds AB, Lansing TJ, Parsons JT. Activation of pp60c-src transforming potential by mutations altering the structure of an amino terminal domain containing residues 90-95. Oncogene Res. 1988;3(4):343–355. [PubMed]
  • Prywes R, Foulkes JG, Rosenberg N, Baltimore D. Sequences of the A-MuLV protein needed for fibroblast and lymphoid cell transformation. Cell. 1983 Sep;34(2):569–579. [PubMed]
  • Rein A, McClure MR, Rice NR, Luftig RB, Schultz AM. Myristylation site in Pr65gag is essential for virus particle formation by Moloney murine leukemia virus. Proc Natl Acad Sci U S A. 1986 Oct;83(19):7246–7250. [PubMed]
  • Rosenberg N, Witte ON. The viral and cellular forms of the Abelson (abl) oncogene. Adv Virus Res. 1988;35:39–81. [PubMed]
  • Sadowski I, Stone JC, Pawson T. A noncatalytic domain conserved among cytoplasmic protein-tyrosine kinases modifies the kinase function and transforming activity of Fujinami sarcoma virus P130gag-fps. Mol Cell Biol. 1986 Dec;6(12):4396–4408. [PMC free article] [PubMed]
  • Sanger F, Nicklen S, Coulson AR. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. [PubMed]
  • Schiff-Maker L, Burns MC, Konopka JB, Clark S, Witte ON, Rosenberg N. Monoclonal antibodies specific for v-abl- and c-abl-encoded molecules. J Virol. 1986 Mar;57(3):1182–1186. [PMC free article] [PubMed]
  • Sefton BM, Trowbridge IS, Cooper JA, Scolnick EM. The transforming proteins of Rous sarcoma virus, Harvey sarcoma virus and Abelson virus contain tightly bound lipid. Cell. 1982 Dec;31(2 Pt 1):465–474. [PubMed]
  • Shields A, Witte WN, Rothenberg E, Baltimore D. High frequency of aberrant expression of Moloney murine leukemia virus in clonal infections. Cell. 1978 Jul;14(3):601–609. [PubMed]
  • Shtivelman E, Lifshitz B, Gale RP, Canaani E. Fused transcript of abl and bcr genes in chronic myelogenous leukaemia. Nature. 1985 Jun 13;315(6020):550–554. [PubMed]
  • Shtivelman E, Lifshitz B, Gale RP, Roe BA, Canaani E. Alternative splicing of RNAs transcribed from the human abl gene and from the bcr-abl fused gene. Cell. 1986 Oct 24;47(2):277–284. [PubMed]
  • Smith MR, DeGudicibus SJ, Stacey DW. Requirement for c-ras proteins during viral oncogene transformation. Nature. 1986 Apr 10;320(6062):540–543. [PubMed]
  • Soekarman D, van Denderen J, Hoefsloot L, Moret M, Meeuwsen T, van Baal J, Hagemeijer A, Grosveld G. A novel variant of the bcr-abl fusion product in Philadelphia chromosome-positive acute lymphoblastic leukemia. Leukemia. 1990 Jun;4(6):397–403. [PubMed]
  • Stahl ML, Ferenz CR, Kelleher KL, Kriz RW, Knopf JL. Sequence similarity of phospholipase C with the non-catalytic region of src. Nature. 1988 Mar 17;332(6161):269–272. [PubMed]
  • Takebe Y, Seiki M, Fujisawa J, Hoy P, Yokota K, Arai K, Yoshida M, Arai N. SR alpha promoter: an efficient and versatile mammalian cDNA expression system composed of the simian virus 40 early promoter and the R-U5 segment of human T-cell leukemia virus type 1 long terminal repeat. Mol Cell Biol. 1988 Jan;8(1):466–472. [PMC free article] [PubMed]
  • Wagner EF, Vanek M, Vennström B. Transfer of genes into embryonal carcinoma cells by retrovirus infection: efficient expression from an internal promoter. EMBO J. 1985 Mar;4(3):663–666. [PubMed]
  • Watanabe SM, Witte ON. Site-directed deletions of Abelson murine leukemia virus define 3' sequences essential for transformation and lethality. J Virol. 1983 Mar;45(3):1028–1036. [PMC free article] [PubMed]
  • Whitlock CA, Witte ON. 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. [PubMed]
  • Ziegler SF, Whitlock CA, Goff SP, Gifford A, Witte ON. Lethal effect of the Abelson murine leukemia virus transforming gene product. Cell. 1981 Dec;27(3 Pt 2):477–486. [PubMed]

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