Abstract
Arrested differentiation is a hallmark of progenitor cell leukemias as well as many other types of human cancer. It is hypothesized that such progenitor cell cancers express oncoproteins that block differentiation. The E2A-Pbx1 oncoprotein that results from the t(1;19) chromosomal translocation of childhood pre-B cell acute lymphoblastic leukemia (pre-B ALL) is a fascinating oncoprotein because it blocks differentiation and physically interacts with homeodomain proteins, which are effectors of normal differentiation. These properties suggest the attractive hypothesis that E2A-Pbx1 blocks pre-B cell differentiation by interfering with the ability of other homeodomain proteins to orchestrate terminal B cell differentiation.
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References
Balling R, Mutter G, Gruss P, Kessel M (1989) Craniofacial abnormalities induced by ectopic expression of the homeobox gene Hox-1.1 in transgenic mice. Cell 58: 337 – 348
Burglin TR, Ruvkun G (1992) New motif in PBX genes. Nature genetics 1: 319 – 320
Carroll A, Crist W, Parmley R, Roper M, Cooper M, Finley W (1984) Pre-B cell leukemia associated with chromosome translocation 1;19. Blood 63: 721 – 724
Chan S-K, Jaffe L, Capovilla M, Botas J, Mann R (1994) The DNA binding specificity of Ultrabithorax is modulated by cooperative interactions with extradenticle, another homeoprotein. Cell 78: 603 – 615
Charite J, Graaff W, Shen S, Deschamps J (1994) Ectopic expression of Hoxb-8 causes duplication of the ZPA in the forelimb and homeotic transformation of axial structures. Cell 78: 589 – 601
Chisaka O, Capecchi M (1991) Regionally restricted developmental defects resulting from targeted disruption of the mouse homeobox gene hox-1.5. Nature 350: 473 – 479
Chisaka O, Musci T, Capecchi M (1992) Developmental defects of the ear, cranial nerves and hindbrain resulting from targeted disruption of the mouse homeobox gene Hox-1.6. Nature 355: 516 – 520
Condie B, Capecchi M (1993) Mice homozygous for a targeted disruption of Hoxd-3 (Hox-4.1) exhibitanterior transformation of the first and second cervical vertebrae, the atlas and axis. Development 110: 579 – 595
Crist W, Carroll A, Shuster J, Behm F, Whitehead M, Vietti T, Look A, Mahoney D, Ragab A, Pullen D, Land V (1990) Poor prognosis of children with pre-B acute lymphoblastic leukemia is associated with the t(1;19)(q23;p13): A pediatric oncology group study. Blood 76: 117 – 122
Dedera DA, Waller EK, Lebrun DP, Sen-Majumdar A, Stevens ME, Barsh GS, Cleary ML (1993) Chimeric homeobox gene E2A-Pbx1 induces proliferation, apoptosis, and malignant lymphomas in transgenic mice. Cell 74: 833 – 843
Dolle P, Dierich A, LeMeur M, Schimmang T, Schuhbaur B, Chambón P, Duboule D (1993) Disruption of the Hoxd-13 gene induces localized heterochrony leading to mice with neotenic limbs. Cell 75: 431 – 441
Henthorn P, Kiledijan M, Kadesch T (1990) Two distinct transcription factors that binds the immunoglobulin enhancer mE5/kE2 motif. Science 247: 467 – 170
Hunger SP, Galili N, Carroll AJ, Crist WM, Link MP, Cleary ML (1991) The t(1;19)(q23;p13) results in consistent fusion of E2A and PBX1 coding sequences in acute lymphoblastic leukemias. Blood 77: 687 – 693
Jeannotte L, Lemieux M, Charron J, Poirier F, Robertson E (1993) Specification of axial identity in the mouse: role of the Hoxa-5(Hox1.3) gene. Genes Dev 7: 2085 - 2096
Jegalian B, De Robertis E (1992) Homeotic transformations in the mouse induced by overexpression of a human Hox3.3 transgene. Cell 71: 901 – 910
Johnson A (1992) A combinatorial regulatory circuit in budding yeast. Transcriptional Regulation 2: 975 – 1007
Jones F, Prediger E, Bittner D, DeRobertis E, Edelman G (1992) Cell adhesion molecules as targets for Hox genes: Neural cell adhesion molecule promoter activity is modulated by cotransfection with Hox- 2.5 and -2.4. Proc Natl Acad Sci USA 89: 2086 – 2090
Kagawa N, Ogo A, Takahashi Y, Iwamatsu A, Waterman MR (1994) A cAMP-regulatory sequence (CRS1) of CYP17 is a cellular target for the homeodomain protein Pbx1. J Biol Chem 269: 18716 – 18719
Kamps MP, Murre C, Sun X, Baltimore D (1990) A new homeobox gene contributes the DNA binding domain of the t(1;19) translocation proteins in pre-B ALL. Cell 60: 547 – 555
Kamps MP, Look AT, Baltimore D (1991) The human t(1;19) translocation in pre-B ALL produces multiples nuclear E2A-Pbx1 fusion proteins with differing transforming potentials. Genes Dev 5: 358 – 368
Kamps MP, Baltimore D (1993) 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 13: 351 – 357
Kamps MP, Wright DD (1994) Oncoprotein E2A-Pbx1 immortalizes cultured myeloid progenitors without abrogating their factor-dependence. Oncogene 9: 3159 – 3166
Kamps MP, Wright DD, Lu Q (1995) DNA-binding by oncoprotein E2A-Pbx1 is important for blocking differentiation but dispensable for fibroblast transformation. Oncogene 12: 19 – 30
Kessel M, Balling R, Gruss P (1990) Variations of cervical vertebrae after expression of a Hox 1.1 transgene in mice. Cell 61: 301 – 308
Knight S, Tamai K, Kosman D, Thiele D (1994) Identification and analysis of a saccharomyces cerevisiae copper homeostasis gene encoding a homeodomain protein. Mol Cell Biol 14: 7792 – 7804
Knoepfler PS, Kamps MP (1995) The pentapeptide motif of Hox proteins is required for cooperative DNA-binding with Pbx1, physically contacts Pbx1 and enhances DNA-binding by Pbxl. Mo1 Cell Biol 15: 5811 – 5819
Lai J-S, Herr W (1992) Ethidium bromide provides a simple tool for identifying genuine DNA-in- dependent protein associations. Proc Natl Acad Sci USA 89: 6958 – 6962
Lebrun DP, Cleary ML (1994) Fusion with E2A alters the transcriptional properties of the homeodomain protein PBX1 in t(1;19) leukemias. Oncogene 9: 1641 – 1647
LeMouellic H, Lallemand V, Brulet P (1992) Homeosis in the mouse induced by a null mutation in the Hox-3.1 gene. Cell 69: 251 – 264
Levine M, Hoey T (1988) Homeobox proteins as a sequence-specific transcription factors. Cell 55: 537 – 540
Lu Q, Wright DD, Kamps MP (1994) Fusion with E2A converts the Pbxl homeodomain protein into a constitutive transcriptional activator in human leukemias carrying the t(1;19) translocation. Mol Cell Biol 6: 3938 – 3948
Lu Q, Knoepfler P, Scheele J, Wright DD, Kamps MP (1995) Both Pbx1 and E2A-Pbx1 bind the DNA motif ATCAATCAA cooperatively with the products of multiple murine Hox genes, some of which are themselves oncogenes. Mol Cell Biol 15: 3786 – 3795
Lufkin T, Dierich A, LeMeur M, Mark M, Chambon P (1991) Disruption of the Hox-1.6 homeobox gene results in defects in a region corresponding to its rostral domain of expression. Cell 66: 1105 – 1119
Lufkin T, Mark M, Hart C, Dolle P, LeMeur M, Chambon P (1992) Homeotic transformation of the occipital bones of the skull by ectopic expression of a homeobox gene. Nature 359: 835 - 841
Lund J, Ahlgren R, Wu D, Kagimoto M, Simpson E, Waterman M (1990) Transcriptional regulation of the bovine CYP17 (P-45017a) gene. J Biol Chem 265: 3304 – 3312
Mak A, Johnson AD (1993) The carboxyl-terminal tail of the homeodomain protein α2 is required for function with a second homeodomain protein. Genes Dev 7: 1862 – 1870
Mathews C, Detmer K, Boncinelli E, Lawrence H, Largmen C (1991) Erythroid-restricted expression of homeobox genes of the human HOX 2 locus. Blood 78: 2248 – 2252
McGinnis W, Krumlauf R (1992) Homeobox genes and axial patterning. Cell 68: 283 – 302
Maulbecker CC, Gruss P (1993) The oncogenic potential of deregulated homeobox genes. Cell Growth and Dif4: 431 – 141
Mellentin JD, Murre C, Donlon TA, McCaw PS, Smith S, Caroli A, McDonald M, Baltimore D, Cleary M (1989) The gene for enhancer binding proteins E12/E47 lies at the t(1;19) breakpoint in acute leukemias. Science 246: 379 – 382
Monica K, Galili N, Nourse J, Saltman D, Cleary ML (1991) PBX2 and PBX3, new homeobox genes with extensive homology to the human proto-oncogene PBX1 Mol Cell Biol 11: 6149 – 6157
Monica K, LeBrun DP, Dedera D, Brown R, Cleary ML (1994) Transformation properties of the E2A- Pbx1 chimeric oncoprotein: Fusion with E2A is essential, but the Pbx1 homeodomain is dispensable. Mol Cell Biol 14: 8304 – 8314
Morgan B, Izpisua-Belmonte J, Duboule D, Tabin C (1992) Targeted misexpression of Hox-4.6 in the avian limb bud causes apparent homeotic transformations. Nature 358: 236 – 239
Murre C, McCaw P, Baltimore D (1989) A new DNA binding and dimerization motif in immunoglobulin enhancer binding, daughterless, MyoD, and Myc proteins. Cell 56: 777 – 783
Nourse J, Mellentin JD, Galili N, Wilkinson J, Stanbridge E, Smith SD, Cleary ML (1990) Chromosomal translocation t(1; 19) results in synthesis of a homeobox fusion mRNA that codes for a potential chimeric transcription factor. Cell 60: 535 – 546
Numata S, Kato K, Horibe K (1993) New E2A-Pbx1 fusion transcript in a patient with t(1;19)(q23;p13) acute lymphoblastic leukemia. Leukemia 7: 1441 – 1444
Perkins A, Cory S (1993) Conditional immortalization of mouse myelomonocytic, megakaryocytic and mast cell progenitors by the Hox-2.4 homeobox gene. EMBO J 12: 3835 – 3846
Perkins A, Kongsuwan K, Visvader J, Adams JM, Cory S (1990) Homeobox gene expression plus autocrine growth factor production elicits myeloid leukemia. Proc Natl Acad Sci 87: 8398 – 8402
Petrini M, Quaranta M, Testa U, Samoggia P, Tritarelli E, Care A, Cianetti L, Valtieri M, Barletta C, Peschle C (1992) Expression of selected human HOX-2 genes in B/T acute lymphoid leukemia and interleukin-2/interleukin-1 b-stimulated natural killer lymphocytes. Blood 80: 185 – 193
Pollock R, Jay G, Bieberich C (1992) Altering the boundaries of Hox3.1 expression: evidence for antipodal gene regulation. Cell 71: 911 – 923
Privitera E, Kamps MP, Hayashi Y, Inaba T, Shapiro LH, Raimondi SC, Behm F, Hendershot L, Carroll AJ, Baltimore D, Look AT (1992) Different molecular consequences of the 1; 19 chromosomal translocations in childhood B-cell precursor acute lumphoblastic leukemia. Blood 79: 1781 – 1788
Privitera E, Luciano A, Ronchetti D, Arico M, Santostasi T, Basso G, Biondi A (1994) Molecular variants of the 1; 19 chromosomal translocation in pediatric acute lymphoblastic leukemia (ALL). Leukemia 8: 554 – 559
Qian Y, Otting G, Furukubo-Tokunaga K, Affolter M, Gehring W, Wuthrich K (1992) NMR structure determination reveals that the homeodomain is connected through a flexible linker to the main body in the Drosophila Antennapedia protein. Proc Natl Acad Sci USA 89: 10738 – 10742
Raimondi S, Behm F, Roberson P, Williams D, Pui C, Crist W, Look A, Rivera G (1990) Cytogenetics of pre-B acute lymphoblastic leukemia with emphasis on prognostic implications of the t(1;19). J Clin Oncol 8: 1380 – 1390
Ramirez-Solis R, Zheng H, Whiting J, Krumlauf R, Bradley A (1993) Hoxb-4 (Hox-2.6) mutant mice show homeotic transformation of a cervical vertebra and defects in the closure of the sternal rudiments. Cell 73: 279 – 294
Rauskolb C, Peifer M, Wieschaus E (1993) Extradenticle, a regulator of homeotic gene activity, is a homologue of the homeobox-containing human proto-oncogene Pbx1. Cell 74: 1101 – 1112
Rauskolb C, Wieschaus E (1994) Coordinate regulation of downstream genes by extradenticle and the homeotic selector proteins. EMBO J 13: 3561 – 3569
Scott MP, Tamkun JW, Hartzel GW III (1989) The structure and function of the homeodomain. Biochim Biophys Acta 989: 25 – 48
Van Dijk MA, Voorhoeve P, Murre C (1993) Pbx1 is converted into a transcriptional activator upon acquiring the N-terminal region of E2A in pre-B cell acute lymphoblastoid leukemia. Proc Natl Acad Sci USA 90: 6061 – 6065
Van Dijk MA, Murre C (1994) Extradenticle raises the DNA-binding specificity of homeotic selector gene products. Cell 78: 617–624
Vershon AK, Johnson AD (1993) A short, disordered protein region mediates interactions between thehomeodomain of the yeast α2 protein and the MCM1 protein. Cell 72: 105 – 112
Vogler L, Crist W, Boekman D, Pearl E, Lawton A, Cooper M (1978) A new phenotype of childhood lymphoblastic leukemia. N Eng J Med 298: 872–878
Williams D, Look A, Meivin S, Roberson P, Dahl G, Flake T, Stass S (1984) New chromosomal translocations correlate with specific immunophenotypes of childhood acute lymphoblastic leukemia. Cell 36: 101 – 109
Wolberger C, Vershon A, Liu B, Johnson A, Pabo C (1991) Crystal structure of a MATa2 homeodomain-operator complex suggests a general model for homeodomain-DNA interactions. Cell 67: 517 – 528
Wright CVE, Cho KWY, Oliver G, DeRobertis EM (1989) Vertebrate homeodomain proteins: families of region-specific transcription factors. Trends Biochem Sci 14: 52 – 56
Zappavigna V, Sartori D, Mavilio F (1994) Specificity of HOX protein function depends on DNA-protein and protein-protein interactions, both mediated by the horneo domain. Genes Dev 8: 732 – 744
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Kamps, M.P. (1997). E2A-Pbx1 Induces Growth, Blocks Differentiation, and Interacts with Other Homeodomain Proteins Regulating Normal Differentiation. In: Rauscher, F.J., Vogt, P.K. (eds) Chromosomal Translocations and Oncogenic Transcription Factors. Current Topics in Microbiology and Immunology, vol 220. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-60479-9_2
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DOI: https://doi.org/10.1007/978-3-642-60479-9_2
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