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Proc Natl Acad Sci U S A. Jul 1, 1993; 90(13): 6061–6065.
PMCID: PMC46867

Pbx1 is converted into a transcriptional activator upon acquiring the N-terminal region of E2A in pre-B-cell acute lymphoblastoid leukemia.

Abstract

Twenty-five percent of human pediatric pre-B-cell acute lymphoblastic leukemias (ALLs) are characterized by the t(1;19)(q23;p13.3) chromosomal translocation. This translocation joins the 5' region of the E2A gene to the 3' region of the Pbx1 gene. The protein encoded by this chimeric gene contains the N-terminal transcriptional activation domain of E2A fused to the C-terminal region of Pbx1, which contains a putative homeodomain. Here we show that the Pbx1 homeodomain preferentially binds the sequence ATCAATCAA. We further show that promoters containing Pbx1-binding sites are activated by the chimeric E2A-Pbx1 protein but not by Pbx1. These results indicate that the t(1;19) translocation converts a nonactivating DNA-binding protein into a potent transcriptional activator, suggesting an unusual mechanism for oncogenic transformation.

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  • Henthorn P, Kiledjian M, Kadesch T. Two distinct transcription factors that bind the immunoglobulin enhancer microE5/kappa 2 motif. Science. 1990 Jan 26;247(4941):467–470. [PubMed]
  • Murre C, McCaw PS, Baltimore D. A new DNA binding and dimerization motif in immunoglobulin enhancer binding, daughterless, MyoD, and myc proteins. Cell. 1989 Mar 10;56(5):777–783. [PubMed]
  • Nelson C, Shen LP, Meister A, Fodor E, Rutter WJ. Pan: a transcriptional regulator that binds chymotrypsin, insulin, and AP-4 enhancer motifs. Genes Dev. 1990 Jun;4(6):1035–1043. [PubMed]
  • Kadesch T. Helix-loop-helix proteins in the regulation of immunoglobulin gene transcription. Immunol Today. 1992 Jan;13(1):31–36. [PubMed]
  • Weintraub H, Davis R, Tapscott S, Thayer M, Krause M, Benezra R, Blackwell TK, Turner D, Rupp R, Hollenberg S, et al. The myoD gene family: nodal point during specification of the muscle cell lineage. Science. 1991 Feb 15;251(4995):761–766. [PubMed]
  • Quong MW, Massari ME, Zwart R, Murre C. A new transcriptional-activation motif restricted to a class of helix-loop-helix proteins is functionally conserved in both yeast and mammalian cells. Mol Cell Biol. 1993 Feb;13(2):792–800. [PMC free article] [PubMed]
  • Mellentin JD, Smith SD, Cleary ML. lyl-1, a novel gene altered by chromosomal translocation in T cell leukemia, codes for a protein with a helix-loop-helix DNA binding motif. Cell. 1989 Jul 14;58(1):77–83. [PubMed]
  • Begley CG, Aplan PD, Denning SM, Haynes BF, Waldmann TA, Kirsch IR. 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. [PMC free article] [PubMed]
  • Chen Q, Cheng JT, Tasi LH, Schneider N, Buchanan G, Carroll A, Crist W, Ozanne B, Siciliano MJ, 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. [PMC free article] [PubMed]
  • Hunger SP, Ohyashiki K, Toyama K, Cleary ML. Hlf, a novel hepatic bZIP protein, shows altered DNA-binding properties following fusion to E2A in t(17;19) acute lymphoblastic leukemia. Genes Dev. 1992 Sep;6(9):1608–1620. [PubMed]
  • Inaba T, Roberts WM, Shapiro LH, Jolly KW, Raimondi SC, Smith SD, Look AT. Fusion of the leucine zipper gene HLF to the E2A gene in human acute B-lineage leukemia. Science. 1992 Jul 24;257(5069):531–534. [PubMed]
  • Carroll AJ, Crist WM, Parmley RT, Roper M, Cooper MD, Finley WH. Pre-B cell leukemia associated with chromosome translocation 1;19. Blood. 1984 Mar;63(3):721–724. [PubMed]
  • Williams DL, Look AT, Melvin SL, Roberson PK, Dahl G, Flake T, Stass S. New chromosomal translocations correlate with specific immunophenotypes of childhood acute lymphoblastic leukemia. Cell. 1984 Jan;36(1):101–109. [PubMed]
  • Kamps MP, Murre C, Sun XH, Baltimore D. A new homeobox gene contributes the DNA binding domain of the t(1;19) translocation protein in pre-B ALL. Cell. 1990 Feb 23;60(4):547–555. [PubMed]
  • Nourse J, Mellentin JD, Galili N, Wilkinson J, Stanbridge E, Smith SD, Cleary ML. Chromosomal translocation t(1;19) results in synthesis of a homeobox fusion mRNA that codes for a potential chimeric transcription factor. Cell. 1990 Feb 23;60(4):535–545. [PubMed]
  • Monica K, Galili N, Nourse J, Saltman D, Cleary ML. PBX2 and PBX3, new homeobox genes with extensive homology to the human proto-oncogene PBX1. Mol Cell Biol. 1991 Dec;11(12):6149–6157. [PMC free article] [PubMed]
  • Kamps MP, Look AT, Baltimore D. The human t(1;19) translocation in pre-B ALL produces multiple nuclear E2A-Pbx1 fusion proteins with differing transforming potentials. Genes Dev. 1991 Mar;5(3):358–368. [PubMed]
  • Flegel WA, Singson AW, Margolis JS, Bang AG, Posakony JW, Murre C. Dpbx, a new homeobox gene closely related to the human proto-oncogene pbx1 molecular structure and developmental expression. Mech Dev. 1993 May;41(2-3):155–161. [PubMed]
  • Gilman MZ, Wilson RN, Weinberg RA. Multiple protein-binding sites in the 5'-flanking region regulate c-fos expression. Mol Cell Biol. 1986 Dec;6(12):4305–4316. [PMC free article] [PubMed]
  • Keegan L, Gill G, Ptashne M. Separation of DNA binding from the transcription-activating function of a eukaryotic regulatory protein. Science. 1986 Feb 14;231(4739):699–704. [PubMed]
  • Blackwell TK, Weintraub H. Differences and similarities in DNA-binding preferences of MyoD and E2A protein complexes revealed by binding site selection. Science. 1990 Nov 23;250(4984):1104–1110. [PubMed]
  • Murre C, McCaw PS, Vaessin H, Caudy M, Jan LY, Jan YN, Cabrera CV, Buskin JN, Hauschka SD, Lassar AB, et al. Interactions between heterologous helix-loop-helix proteins generate complexes that bind specifically to a common DNA sequence. Cell. 1989 Aug 11;58(3):537–544. [PubMed]
  • Kappler J, White J, Wegmann D, Mustain E, Marrack P. Antigen presentation by Ia+ B cell hybridomas to H-2-restricted T cell hybridomas. Proc Natl Acad Sci U S A. 1982 Jun;79(11):3604–3607. [PMC free article] [PubMed]
  • Travis A, Amsterdam A, Belanger C, Grosschedl R. LEF-1, a gene encoding a lymphoid-specific protein with an HMG domain, regulates T-cell receptor alpha enhancer function [corrected]. Genes Dev. 1991 May;5(5):880–894. [PubMed]
  • Gluzman Y. SV40-transformed simian cells support the replication of early SV40 mutants. Cell. 1981 Jan;23(1):175–182. [PubMed]
  • Maxam AM, Gilbert W. Sequencing end-labeled DNA with base-specific chemical cleavages. Methods Enzymol. 1980;65(1):499–560. [PubMed]
  • Kamps MP, Baltimore D. E2A-Pbx1, the t(1;19) translocation protein of human pre-B-cell acute lymphocytic leukemia, causes acute myeloid leukemia in mice. Mol Cell Biol. 1993 Jan;13(1):351–357. [PMC free article] [PubMed]
  • Angel P, Karin M. The role of Jun, Fos and the AP-1 complex in cell-proliferation and transformation. Biochim Biophys Acta. 1991 Dec 10;1072(2-3):129–157. [PubMed]
  • Blackwell TK, Kretzner L, Blackwood EM, Eisenman RN, Weintraub H. Sequence-specific DNA binding by the c-Myc protein. Science. 1990 Nov 23;250(4984):1149–1151. [PubMed]
  • de Thé H, Chomienne C, Lanotte M, Degos L, Dejean A. The t(15;17) translocation of acute promyelocytic leukaemia fuses the retinoic acid receptor alpha gene to a novel transcribed locus. Nature. 1990 Oct 11;347(6293):558–561. [PubMed]
  • Metz T, Graf T. Fusion of the nuclear oncoproteins v-Myb and v-Ets is required for the leukemogenicity of E26 virus. Cell. 1991 Jul 12;66(1):95–105. [PubMed]
  • de Thé H, Vivanco-Ruiz MM, Tiollais P, Stunnenberg H, Dejean A. Identification of a retinoic acid responsive element in the retinoic acid receptor beta gene. Nature. 1990 Jan 11;343(6254):177–180. [PubMed]
  • Kakizuka A, Miller WH, Jr, Umesono K, Warrell RP, Jr, Frankel SR, Murty VV, Dmitrovsky E, Evans RM. Chromosomal translocation t(15;17) in human acute promyelocytic leukemia fuses RAR alpha with a novel putative transcription factor, PML. Cell. 1991 Aug 23;66(4):663–674. [PubMed]
  • Hanes SD, Brent R. DNA specificity of the bicoid activator protein is determined by homeodomain recognition helix residue 9. Cell. 1989 Jun 30;57(7):1275–1283. [PubMed]
  • Treisman J, Gönczy P, Vashishtha M, Harris E, Desplan C. A single amino acid can determine the DNA binding specificity of homeodomain proteins. Cell. 1989 Nov 3;59(3):553–562. [PubMed]
  • Desplan C, Theis J, O'Farrell PH. The sequence specificity of homeodomain-DNA interaction. Cell. 1988 Sep 23;54(7):1081–1090. [PMC free article] [PubMed]
  • Dolan JW, Fields S. Cell-type-specific transcription in yeast. Biochim Biophys Acta. 1991 Feb 16;1088(2):155–169. [PubMed]

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