Abstract
Several recurring chromosomal translocations involve the AML1 gene at 2lq22 in myeloid leukemias resulting in fusion mRNAs and chimeric proteins between AML1 and a gene on the partner chromosome. AMLl corresponds to CBFA2, one of the DNA-binding subunits of the enhancer core binding factor CBF. Other CBF DNA-binding subunits are CBFA1 and CBFA3, also known as AML3 and AML2. AML1, AML2 and AML3 are each characterized by a conserved domain at the amino end, the runt domain, that is necessary for DNA-binding and protein dimerization, and by a transactivation domain at the carboxyl end. AML1 was first identified as the gene located at the breakpoint junction of the 8;21 translocation associated with acute myeloid leukemia. The t(8;21)(q22;q22) interrupts AML1 after the runt homology domain, and fuses the 5’ part of AML1 to almost all of ETO, the partner gene on chromosome 8. AML1 is an activator of several myeloid promoters; however, the chimeric AML1/ETO is a strong repressor of some AML 1-dependent promoters.
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References
Miyoshi H, Shimizu K, Kozu T, Maseki N, Kaneko Y and Ohki M. (1991) The t(8;21) breakpoints on chromosome 21 in acute myeloid leukemia are clustered within a limited region of a novel gene, AML1. Proc Natl Acad Sci USA: 88 10431–10435
Nucifora G, Begy CR, Kobayashi H, Claxton D, Pedersen-Bjergaard J, Parganas E, Ihle J, and Rowley JD (1994) Consistent intergenic splicing and production of multiple transcripts between AML1 at 21q22 and unrelated genes at 3q26 in the (3;21)(q26;q22) translocation. Proc Natl Acad Sci USA 91:4004–4008.
Roulston D, Nucifora G, Dietz-Band J, LeBeau MM and Rowley JD [1993] Detection of rare 21q22 translocation breakpoints within the AML1 gene in myeloid neoplasms by fluorescence in situ hybridization. Blood 82 (Suppl. 1): 532a
Erickson P, Gao J, Chang K-S, Look T, Whisenant E, Raimon S, Lasher R, Trujillo J, Rowley JD and Drabkin H (1992) Identification of breakpoints in t(8;21) AML and isolation of a fusion transcript with similarity to Drosophila segmentation gene runt. Blood 80:1825- 1831
Levanon D, Negreanu V, Bernstein Y, Bar-Am I, Avivi L and Groner Y. AML1, AML2 and AML3, the human members of the runt domain gene-family: cDNA structure, expression and chromosomal localization. (1994) Genomics 23:425–430
Wijmenga C, Speck N A, Dracopoli N C, Lewis A F, Hofker M H and Collins F S (1995) Identification of a new murine runt domain-containing gene, Cbfa3, and localization of the human homolog, CBFA3, to chromosome Ip35-ter. Genomics 26:611–614
Nucifora G, Birn D, Espinosa R, LeBeau M, Erickson P, Roulston D, McKeithan TW, Drabkin H and Rowley JD (1993) Involvement of the AML1 gene in the t(3;21) in therapy related leukemia and in chronic myeloid leukemia in blast crisis. Blood 81:2728–2733
Meyers S, Lenny N and Hiebert S. (1995) The t(8;21) fusion protein interferes with AML1B dependent transcriptional activation. Mol Cell Biol 15:1974–1982
Kagoshima H, Shigesada K, Satake M, Ito Y, Miyoshi M, Ohki M, Pepling M and Gergen P.(1993) The Runt domain identifies a new family of heterodimeric transcriptional activators.Trends Genet. 9:338–341
Liu P, Tarle SA, Hajra A, Claxton DF, Marlton P, Freedman M, Siciliano MJ and Collins FS (1993) Fusion between transcription factor CBFβ/PEBP2β and α myosin heavy chain in acute myeloid leukemia. Science 261:1041–1044
Nucifora G and Rowley JDR. AML1 and the 8;21 and 3;21 translocations in acute and chronic myeloid leukemia. Blood, in press
Golub TR, Barker GF, Bohlander SK, Hiebert SW, Ward DC, Bray-Ward P, Morgan E, Raimondi SC, Rowley JD and Gilliland DG. Fusion of the TEL gene on 12p13 to the AML1 gene on 21q22 in acute lymphoblastic leukemia. Proc Natl Acad Sci USA, in press.
Frank R, Zhang J, Hiebert S, Meyers S and Nimer S (1994) AML1B but not the AML1/ETO fusion protein can transactivate the GM-CSF promoter. Blood 84(Suppl. 1):229a
Zhang D-R, Fujioka K-I, Hetherington CJ, Shapiro LH, Look AT and Tenen DG. Identification of a region which directs monocytic activity of the CSF-1 (M-CFS) receptor promoter and binds PEBP2/CBF (AML1). Mol Cell Biol, in press.
Gottschalk LR and Leiden JM (1990) Identification and functional characterization of the human T-cell receptor β gene transcriptional enhancer: common nuclear proteins interact with the transcriptional regulatory elements of the T-cell receptor αand β genes. Mol Cell Biol 10:5486–5495
Kappes DJ, Browne CP and Tonegawa S (1991) Identification of a T-cell-specific enhancer at the locus encoding T-cell antigen receptor δ chain. Proc Natl Acad Sci USA 88:2204–2208
Speck NA, Renjifo B, Golemis E, Fredrickson TN, Hartley JW and Hopkins N (1990) Mutation of the core of adjacent L Vb elements of the Moloney murine leukemia virus enhancer alters disease specificity. Genes Dev 4:233–242
Wang S and Speck NA (1992) Purification of core-binding factor, a protein that binds the conserved core site in murine leukemia virus enhancers. Mol Cell Biol 12:89–102
Tanaka T, Mitani K, Kurokawa M, Ogawa S, Tanaka K, Nishida J, Yazaki Y and Hirai H (1995) Dual functions of the AML1/EVI1 chimeric protein in the mechnism of leukemogenesis in t(3;21) leukemia. Mol Cell Biol 15:2383–2392
Rubin CM, Larson RA, Anastasi J, Winter JN, Thangavelu M, Vardiman J, Rowley JD and LeBeau MM (1990) t(3;21)(q26;q22): a recurring chromosomal abnormality in therapy-related myelodysplastic syndrome and acute myeloid leukemia. Blood 76:2594–2599
Rubin CM, Larson RA, Bitter MA, Carrino JJ, LeBeau MM, Diaz MO and Rowley JD (1987) Association of a chromosomal translocation with the blast phase of chronic myelogenous leukemia. Blood 70:1338–1344
Nucifora G, Begy CR, Erickson P, Drabkin H A and Rowley JD. (1993) The 3;21 translocation in myelodysplasia results in a fusion transcript between the AMLI gene and the gene for EAP, a highly conserved protein associated with the Epstein-Barr virus small RNA EBER-l. Proc Natl Acad Sci USA 90: 7784–7788
Mitani K, Ogawa S, Tanaka T, Miyoshi H, Kurokawa MK, Mano H, Yazaki Y, Ohki M and Hirai H. (1994) Generation of the AML1 /EVI1 fusion gene in the t(3;21)(q26;q22) causes blastic crisis in chronic myelocytic leukemia. EMBO J. 13:504–510
Toczyski DPW and Steitz JA (1991) EAP, a highly conserved cellular protein associated with Epstein-Barr virus small RNAs (EBERs) EMBO J. 10:459–466
Toczyski D, Matera AG, Ward DC and Steitz JA The Epstein-Barr virus (EBV) small RNA EBERl binds and relocalizes ribosomal protein L22 in EBV-infected human B lymphocytes (1994) Proc Natl Acad Sci USA 91:3463–3467
Sacchi N, Nisson P, Watkins P, Faustinella F, Wijsman J and Hagemeijer A. (1994) AML1 fusion transcripts in t(3;21) positive leukemia: Evidence of molecular heterogeneity and usage of splicing sites frequently involved in the generation of normal AML1 transcripts.Genes Chromosomes Cancer 11:226–231
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© 1996 Springer-Verlag Berlin Heidelberg
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Zent, C. et al. (1996). Rearrangement of the AML1/CBFA2 Gene in Myeloid Leukemia with the 3;21 Translocation:Expression of Co-Existing Multiple Chimeric Genes with Similar Functions as Transcriptional Repressors, but with Opposite Tumorigenic Properties. In: Wolff, L., Perkins, A.S. (eds) Molecular Aspects of Myeloid Stem Cell Development. Current Topics in Microbiology and Immunology, vol 211. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-85232-9_24
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DOI: https://doi.org/10.1007/978-3-642-85232-9_24
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