Abstract
AMLl is the most frequent target for chromosomal translocations in acute leukemia. AML-1 binds the canonical DNA sequence TGT/cGGT in concert with core binding factor ß to activate or repress transcription. The chromosomal translocation fusion proteins that disrupt this heterodimeric transcription factor create constitutive repressors. Our work has focused on defining the molecular mechanism of transcriptional regulation by these cancer-associated fusion proteins. We have found that the t(8;21) fusion protein makes multiple contacts with the mSin3A and N- CoR co-repressors. In addition, the fusion protein also contacts histone deacetylases 1, 2, and 3 independent of the co-repressors. The t(12;21) fusion protein also interacts with mSin3A and N-CoR, but appears to interact only with histone deaceylase 3. By contrast, the inv(16) fusion protein appears to act as an AML-1 co-repressor and makes indirect associations with co-repressors and histone deacetylases. Therefore, the use of histone deacetylases may be a common feature of these translocations fusion proteins and may provide an opportunity for therapeutic intervention.
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References
Aronson, B. D., Fisher, A. L., Blechman, K., Caudy, M., and Gergen, J. P. (1997). Groucho-dependent and—independent repression activities of Runt domain proteins, Molecular & Cellular Biology 17, 5581–7.
Chakrabarti, S. R., and Nucifora, G. (1999). The leukemia-associated gene TEL encodes a transcription repressor which associates with SMRT and mSin3A [In Process Citation], Biochem Biophys Res Commun 264, 871–7.
Fenrick, R., Lutterbach, B., Amann, J., Westendorf, J., Downing, J., and Hiebert, S. (1999). Both TEL and AML-1 contribute repression domains to the t(12;21) fusion protein, Mol Cell Biol 19, 6566–6574.
Golub, T. R., Barker, G. F., Bohlander, S. K., Hiebert, S. W., Ward, D. C., Bray-Ward, P., Morgan, E., Rai- mondi, S. C., Rowley, J. D., and Gilliland, D. G. (1995). Fusion of the TEL gene on 12pl3 to the AMLl gene on 21q22 in acute lymphoblastic leukemia, Proceedings of the National Academy of Sciences of the United States of America 92, 4917–21.
Guidez, F., Petrie, K., Ford, A. M., Lu, H., Bennett, C. A., MacGregor, A., Hannemann, J., Ito, Y., Ghysdael, J., Greaves, M., et al (2000). Recruitment of the nuclear receptor corepressor N-CoR by the TEL moiety of the childhood leukemia-associated TEL- AML1 oncoprotein, Blood 96, 2557–61.
Heinzel, T., Lavinsky, R. M., Mullen, T. M., Soderstrom, M., Laherty, C. D., Torchia, J., Yang, W. M., Brard, G., Ngo, S. D., Davie, J. R., et al (1997). A complex containing N-CoR, mSin3 and histone deacetylase mediates transcriptional repression [see comments], Nature 387, 43–8.
Hiebert, S. W., Sun, W., Davis, J. N., Golub, T., Shurtleff, S., Buijs, A., Downing, J. R., Grosveld, G., Roussell, M. F., Gilliland, D. G., et al (1996). The t(12;21) translocation converts AML-IB from an activator to a repressor of transcription, Molecular 8c Cellular Biology 16, 1349–55.
Kanno, Y., Kanno, T., Sakakura, C., Bae, S. C., and Ito, Y. Cytoplasmic sequestration of the polyoma- virus enhancer binding protein 2 (PEBP2)/core binding factor alpha (CBFalpha) subunit by the leukemia- related PEBP2/CBFbeta-SMMHC fusion protein inhibits PEBP2/CBF-mediated transactiva- tion, Mol Cell Biol 18,4252–61.
Liu, P., Tarle, S. A., Hajra, A., Claxton, D. F., Marlton, P., Freedman, M., Siciliano, M. J., and Collins, F. S. (1993). Fusion between transcription factor CBF beta/PEBP2 beta and a myosin heavy chain in acute myeloid leukemia, Science 261, 1041–1044.
Lowenberg, B., Downing, J. R., and Burnett, A. (1999). Acute myeloid leukemia [see comments] [published erratum appears in N Engl J Med 1999 Nov 4;341(19):1484], N Engl J Med 341, 1051–62.
Lutterbach, B., Hou, Y., Durst, K. L., and Hiebert, S. W. The inv(16) encodes an acute myeloid leukemia 1 transcriptional corepressor, Proc Natl Acad Sci USA 96,12822–7.
Lutterbach, B., Sun, D., Schuetz,]., and Hiebert, S. W. (1998a). The MYND motif is required for repression of basal transcription from the multidrug resistance-1 promoter by the t(8;21) fusion protein, Mol Cell Biol 18, 3601–3611.
Lutterbach, B., Westendorf, J. J., Linggi, B., Isaac, S., Seto, E., and Hiebert, S. W. (2000). A mechanism of repression by acute myeloid leukemia-1, the target of multiple chromosomal translocations in acute leukemia, J Biol Chem 275, 651–6.
Lutterbach, B., Westendorf, J. J., Linggi, B., Patten, A., Moniwa, M., Davie, J. R., Huynh, K. D., Bardwell, V.]., Lavinsky, R. M., Rosenfeld, M. G., et al (1998b). ETO, a target of t(8;21) in acute leukemia, interacts with the N-CoR and mSin3 corepressors, Mol Cell Biol 18, 7176–84.
Meyers, S., Lenny, N., and Hiebert, S. W. (1995). The t(8;21) fusion protein interferes with AML-IB- dependent transcriptional activation, Molecular 8c Cellular Biology 15, 1974–82.
Miyoshi, H., Kozu, T., Shimizu, K., Enomoto, K., Maseki, N., Kaneko, Y., Kamada, N., and Ohki, M. (1993). The t(8;21) translocation in acute myeloid leukemia results in production of an AML1-MTG8 fusion transcript, Embo J 12, 2715–2721.
Miyoshi, H., Shimizu, K., Kozu, T., Maseki, N., Kaneko, Y., and Ohki, M. (1991). t(8;21) breakpoints on chromosome 21 in acute myeloid leukemia are clustered within a limited region of a single gene, AMLl, Proc Natl Acad Sci USA 88,10431–10434.
Romana, S. P., Mauchauffe, M., Le Coniat, M., Chuma- kov, I., Le Paslier, D., Berger, R., and Bernard, O. A. (1995). The t(12;21) of acute lymphoblastic leukemia results in a tel-AMLl gene fusion, Blood 85, 3662–70.
Rubnitz, J. E., Downing, J. R., and Pui, C. H. (1999). Significance of the TEL-AML fusion gene in childhood AML [letter], Leukemia 13, 1470 –1.
Westendorf, J. J., Yamamoto, C. M., Lenny, N., Downing, J. R., Selsted, M. E., and Hiebert, S. W. (1998). The t(8;21) fusion product, AML-1/ETO, associates with C/EBP∝, inhibits C/EBP∝-dependent transcription, and blocks granuloctyic differentiation, Mol Cell Biol 18, 322–333.
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Hiebert, S.W., Lutterbach, B., Amann, J., Durst, K., Linggi, B. (2003). The t(8;21), t(12;21), and inv(16) fusion Proteins Contact Co-Repressors and Histone Deacetylase to Repress Transcription. In: Hiddemann, W., Haferlach, T., Unterhalt, M., Büchner, T., Ritter, J. (eds) Acute Leukemias IX. Haematology and Blood Transfusion Hämatologie und Bluttransfusion, vol 41. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-59358-1_6
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DOI: https://doi.org/10.1007/978-3-642-59358-1_6
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