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RUNX1T1  -  runt-related transcription factor 1;...

Homo sapiens

Synonyms: AML1T1, CBFA2T1, CDR, ETO, MTG8, ...
 
 
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Disease relevance of RUNX1T1

 

Psychiatry related information on RUNX1T1

  • Among significant findings were higher cognitive functioning for the TBI group for FSIQ, VIQ and PIQ; elevated scores on MMPI scales 1, 2, 3 and 8 for both groups, and elevated anxiety scores on the MAACL for the ETO group relative to the TBI group [5].
 

High impact information on RUNX1T1

  • A chimaeric protein is synthesized from one of the derivative chromosomes that contains the N terminus of the AML1 transcription factor, including its DNA-binding domain, fused to most of ETO, a protein of unknown function [6].
  • We expressed in leukemia cells containing PML/RARalpha and AML1/ETO N-CoR protein fragments derived from fusion protein/corepressor interaction surfaces [7].
  • Our experiments provide for the first time a direct insight into the chromatin structure of an AML1-ETO-bound target gene [8].
  • Epigenetic consequences of AML1-ETO action at the human c-FMS locus [8].
  • Atrophin-1, the dentato-rubral and pallido-luysian atrophy gene product, interacts with ETO/MTG8 in the nuclear matrix and represses transcription [9].
 

Chemical compound and disease context of RUNX1T1

  • Polymorphism in the 3' untranslated region of MTG8 is associated with obesity in Pima Indian males [10].
  • BCNU [1,3-bis(2-chloroethyl)-1-nitrosourea], a bifunctional (alkylating/carbamoylating) anticancer agent, in noncytotoxic doses (12-50 microM) inhibited drug-induced apoptosis in HT58 human lymphoma cells exposed to etoposide (ETO; 50 microM) as well as in mouse thymocytes exposed to dexamethasone (5 microg/ml) in vitro in 4-h cultures [11].
  • Lithium treatment in ovo: effects on embryonic heart rate, natural death of ciliary ganglion neurons, and brain expression of a highly conserved chicken homolog of human MTG8/ETO [12].
  • PURPOSE: The purpose of this study was to determine the feasibility, toxicity, and early response of patients with clinical group III rhabdomyosarcoma (RMS) to a chemotherapy regimen of etoposide (ETOP), ifosfamide (IFOS), and vincristine (VCR) with hyperfractionated radiation therapy (XRT) [13].
 

Biological context of RUNX1T1

  • We identified two independent subnuclear targeting signals in the N- and C-terminal regions of ETO that together direct ETO to the same binding sites occupied by AML1ETO [14].
  • This effect was dependent on the presence of the ETO zinc finger domain, which recruits corepressors, and could not be rescued by overexpression of co-repressors that normally enhance PLZF repression [15].
  • Further, we identified a 40 amino acid portion of ETO (amino acids 241-280) that was sufficient to cause nuclear import of green fluorescent protein [16].
  • The fusion gene produces a chimeric transcription factor that suppresses the expression of AML1-target genes via the MTG8 part of the chimeric protein, which is thought to be the primary cause of leukemia [17].
  • Here we present six out of 59 children with AML who were positive for AML1/ETO by RT-PCR, but showed no evidence of the classical t(8;21)(q22;q22) by conventional cytogenetics [3].
 

Anatomical context of RUNX1T1

  • Northern analysis using MTG8 (ETO) probes detected 7.8-kb and 6.2-kb RNAs and several minor RNAs in the cell line with t(8;21), but failed to detect any transcripts in a cell line without t(8;21) [18].
  • We found that, instead of the MYND domain, an alternative last exon of MTG8 encoding 27 amino acids in-frame is expressed naturally in human adult testis and in several leukemia cell lines [17].
  • ETO transcripts, present at very low abundance in CD34(+) progenitor cells, were transiently upregulated during erythroid differentiation [19].
  • AML1/ETO transcripts also were demonstrated in a fraction of colony-forming cells of erythroid, granulocyte-macrophage, and/or megakaryocyte lineages in both leukemic and remission marrow [20].
  • Investigations with normal bone marrow reveal AML1 and ETO are coexpressed in megakaryocytes and that each is expressed in a portion of the approximately 10-microns-diameter cells residing there [21].
 

Associations of RUNX1T1 with chemical compounds

  • Mutational analysis demonstrated that lysine 265 and/or arginine 266 were required for nuclear import of ETO, but that the surrounding basic residues were not critical [16].
  • Recombinant MTG8 protein was first found to be associated with two serine/threonine protein kinases in cell extracts from both HEL cells and a leukemic cell line carrying t(8;21) [22].
  • Endogenous ETO also cosediments on sucrose gradients with mSin3A, N-CoR, and histone deacetylases, suggesting that it is a component of one or more corepressor complexes [23].
  • Here we found that MTG8 interacted with the regulatory subunit of type II cyclic AMP-dependent protein kinase (PKA RIIalpha) [24].
  • Depsipeptide (FR 901228) promotes histone acetylation, gene transcription, apoptosis and its activity is enhanced by DNA methyltransferase inhibitors in AML1/ETO-positive leukemic cells [25].
 

Physical interactions of RUNX1T1

  • Finally, ETO interacted with PLZF/RAR alpha and enhanced its ability to repress through the RARE [15].
  • Thus, we hypothesized that DNMT1 is also part of the transcriptional repressor complex recruited by RUNX1/MTG8 [26].
  • It is shown that two highly conserved domains of ETO interact with repression domains I and III of N-CoR [27].
  • Moreover, ETO is nuclear matrix attached at sites coincident with histone deacetylase enzymes and mSin3a [28].
  • In addition, we demonstrated that heat shock protein 90 (HSP90) specifically binds to the amino-terminal domain of MTG8 in vitro and in vivo [22].
 

Regulatory relationships of RUNX1T1

  • The Leukemia-associated ETO homologues are differently expressed during hematopoietic differentiation [19].
  • This observation provides a mechanism for how the AML1/ETO fusion may inhibit expression of AML1-responsive target genes and disturb normal hematopoiesis [29].
  • The AML1/ETO fusion protein activates transcription of BCL-2 [30].
 

Other interactions of RUNX1T1

 

Analytical, diagnostic and therapeutic context of RUNX1T1

References

  1. The ETO protein disrupted in t(8;21)-associated acute myeloid leukemia is a corepressor for the promyelocytic leukemia zinc finger protein. Melnick, A.M., Westendorf, J.J., Polinger, A., Carlile, G.W., Arai, S., Ball, H.J., Lutterbach, B., Hiebert, S.W., Licht, J.D. Mol. Cell. Biol. (2000) [Pubmed]
  2. Oligomerization of ETO is obligatory for corepressor interaction. Zhang, J., Hug, B.A., Huang, E.Y., Chen, C.W., Gelmetti, V., Maccarana, M., Minucci, S., Pelicci, P.G., Lazar, M.A. Mol. Cell. Biol. (2001) [Pubmed]
  3. Cryptic chromosomal aberrations leading to an AML1/ETO rearrangement are frequently caused by small insertions. Gamerdinger, U., Teigler-Schlegel, A., Pils, S., Bruch, J., Viehmann, S., Keller, M., Jauch, A., Harbott, J. Genes Chromosomes Cancer (2003) [Pubmed]
  4. ETO protein of t(8;21) AML is a corepressor for Bcl-6 B-cell lymphoma oncoprotein. Chevallier, N., Corcoran, C.M., Lennon, C., Hyjek, E., Chadburn, A., Bardwell, V.J., Licht, J.D., Melnick, A. Blood (2004) [Pubmed]
  5. Neurological and emotional sequelae of exposure to ethylene oxide. Patch, P.C., Hartlage, L.C. Int. J. Neurosci. (2001) [Pubmed]
  6. Embryonic lethality and impairment of haematopoiesis in mice heterozygous for an AML1-ETO fusion gene. Yergeau, D.A., Hetherington, C.J., Wang, Q., Zhang, P., Sharpe, A.H., Binder, M., Marín-Padilla, M., Tenen, D.G., Speck, N.A., Zhang, D.E. Nat. Genet. (1997) [Pubmed]
  7. Targeting fusion protein/corepressor contact restores differentiation response in leukemia cells. Racanicchi, S., Maccherani, C., Liberatore, C., Billi, M., Gelmetti, V., Panigada, M., Rizzo, G., Nervi, C., Grignani, F. EMBO J. (2005) [Pubmed]
  8. Epigenetic consequences of AML1-ETO action at the human c-FMS locus. Follows, G.A., Tagoh, H., Lefevre, P., Hodge, D., Morgan, G.J., Bonifer, C. EMBO J. (2003) [Pubmed]
  9. Atrophin-1, the dentato-rubral and pallido-luysian atrophy gene product, interacts with ETO/MTG8 in the nuclear matrix and represses transcription. Wood, J.D., Nucifora, F.C., Duan, K., Zhang, C., Wang, J., Kim, Y., Schilling, G., Sacchi, N., Liu, J.M., Ross, C.A. J. Cell Biol. (2000) [Pubmed]
  10. Polymorphism in the 3' untranslated region of MTG8 is associated with obesity in Pima Indian males. Wolford, J.K., Bogardus, C., Prochazka, M. Biochem. Biophys. Res. Commun. (1998) [Pubmed]
  11. BCNU is a caspase-mediated inhibitor of drug-induced apoptosis. Peták, I., Mihalik, R., Bauer, P.I., Süli-Vargha, H., Sebestyén, A., Kopper, L. Cancer Res. (1998) [Pubmed]
  12. Lithium treatment in ovo: effects on embryonic heart rate, natural death of ciliary ganglion neurons, and brain expression of a highly conserved chicken homolog of human MTG8/ETO. Ikonomov, O.C., Petrov, T., Soden, K., Shisheva, A., Manji, H.K. Brain Res. Dev. Brain Res. (2000) [Pubmed]
  13. A feasibility, toxicity, and early response study of etoposide, ifosfamide, and vincristine for the treatment of children with rhabdomyosarcoma: a report from the Intergroup Rhabdomyosarcoma Study (IRS) IV pilot study. Arndt, C., Tefft, M., Gehan, E., Anderson, J., Jenson, M., Link, M., Donaldson, S., Breneman, J., Wiener, E., Webber, B., Maurer, H. J. Pediatr. Hematol. Oncol. (1997) [Pubmed]
  14. Multiple subnuclear targeting signals of the leukemia-related AML1/ETO and ETO repressor proteins. Barseguian, K., Lutterbach, B., Hiebert, S.W., Nickerson, J., Lian, J.B., Stein, J.L., van Wijnen, A.J., Stein, G.S. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  15. AML-1/ETO fusion protein is a dominant negative inhibitor of transcriptional repression by the promyelocytic leukemia zinc finger protein. Melnick, A., Carlile, G.W., McConnell, M.J., Polinger, A., Hiebert, S.W., Licht, J.D. Blood (2000) [Pubmed]
  16. Nuclear import and subnuclear localization of the proto-oncoprotein ETO (MTG8). Odaka, Y., Mally, A., Elliott, L.T., Meyers, S. Oncogene (2000) [Pubmed]
  17. MYND-less splice variants of AML1-MTG8 (RUNX1-CBFA2T1) are expressed in leukemia with t(8;21). Kozu, T., Fukuyama, T., Yamami, T., Akagi, K., Kaneko, Y. Genes Chromosomes Cancer (2005) [Pubmed]
  18. Junctions of the AML1/MTG8(ETO) fusion are constant in t(8;21) acute myeloid leukemia detected by reverse transcription polymerase chain reaction. Kozu, T., Miyoshi, H., Shimizu, K., Maseki, N., Kaneko, Y., Asou, H., Kamada, N., Ohki, M. Blood (1993) [Pubmed]
  19. The Leukemia-associated ETO homologues are differently expressed during hematopoietic differentiation. Lindberg, S.R., Olsson, A., Persson, A.M., Olsson, I. Exp. Hematol. (2005) [Pubmed]
  20. AML1/ETO-expressing nonleukemic stem cells in acute myelogenous leukemia with 8;21 chromosomal translocation. Miyamoto, T., Weissman, I.L., Akashi, K. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  21. ETO and AML1 phosphoproteins are expressed in CD34+ hematopoietic progenitors: implications for t(8;21) leukemogenesis and monitoring residual disease. Erickson, P.F., Dessev, G., Lasher, R.S., Philips, G., Robinson, M., Drabkin, H.A. Blood (1996) [Pubmed]
  22. Association of MTG8 (ETO/CDR), a leukemia-related protein, with serine/threonine protein kinases and heat shock protein HSP90 in human hematopoietic cell lines. Komori, A., Sueoka, E., Fujiki, H., Ishii, M., Kozu, T. Jpn. J. Cancer Res. (1999) [Pubmed]
  23. ETO, a target of t(8;21) in acute leukemia, interacts with the N-CoR and mSin3 corepressors. Lutterbach, B., Westendorf, J.J., Linggi, B., Patten, A., Moniwa, M., Davie, J.R., Huynh, K.D., Bardwell, V.J., Lavinsky, R.M., Rosenfeld, M.G., Glass, C., Seto, E., Hiebert, S.W. Mol. Cell. Biol. (1998) [Pubmed]
  24. MTG8 proto-oncoprotein interacts with the regulatory subunit of type II cyclic AMP-dependent protein kinase in lymphocytes. Fukuyama, T., Sueoka, E., Sugio, Y., Otsuka, T., Niho, Y., Akagi, K., Kozu, T. Oncogene (2001) [Pubmed]
  25. Depsipeptide (FR 901228) promotes histone acetylation, gene transcription, apoptosis and its activity is enhanced by DNA methyltransferase inhibitors in AML1/ETO-positive leukemic cells. Klisovic, M.I., Maghraby, E.A., Parthun, M.R., Guimond, M., Sklenar, A.R., Whitman, S.P., Chan, K.K., Murphy, T., Anon, J., Archer, K.J., Rush, L.J., Plass, C., Grever, M.R., Byrd, J.C., Marcucci, G. Leukemia (2003) [Pubmed]
  26. Interplay of RUNX1/MTG8 and DNA methyltransferase 1 in acute myeloid leukemia. Liu, S., Shen, T., Huynh, L., Klisovic, M.I., Rush, L.J., Ford, J.L., Yu, J., Becknell, B., Li, Y., Liu, C., Vukosavljevic, T., Whitman, S.P., Chang, K.S., Byrd, J.C., Perrotti, D., Plass, C., Marcucci, G. Cancer Res. (2005) [Pubmed]
  27. The nuclear receptor co-repressor (N-CoR) utilizes repression domains I and III for interaction and co-repression with ETO. Lausen, J., Cho, S., Liu, S., Werner, M.H. J. Biol. Chem. (2004) [Pubmed]
  28. The ETO (MTG8) gene family. Davis, J.N., McGhee, L., Meyers, S. Gene (2003) [Pubmed]
  29. ETO, fusion partner in t(8;21) acute myeloid leukemia, represses transcription by interaction with the human N-CoR/mSin3/HDAC1 complex. Wang, J., Hoshino, T., Redner, R.L., Kajigaya, S., Liu, J.M. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  30. The AML1/ETO fusion protein activates transcription of BCL-2. Klampfer, L., Zhang, J., Zelenetz, A.O., Uchida, H., Nimer, S.D. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  31. The AML1-MTG8 leukemic fusion protein forms a complex with a novel member of the MTG8(ETO/CDR) family, MTGR1. Kitabayashi, I., Ida, K., Morohoshi, F., Yokoyama, A., Mitsuhashi, N., Shimizu, K., Nomura, N., Hayashi, Y., Ohki, M. Mol. Cell. Biol. (1998) [Pubmed]
  32. The p21Waf1 pathway is involved in blocking leukemogenesis by the t(8;21) fusion protein AML1-ETO. Peterson, L.F., Yan, M., Zhang, D.E. Blood (2007) [Pubmed]
  33. AML1-ETO reprograms hematopoietic cell fate by downregulating scl expression. Yeh, J.R., Munson, K.M., Chao, Y.L., Peterson, Q.P., Macrae, C.A., Peterson, R.T. Development (2008) [Pubmed]
  34. Potential involvement of the AML1-MTG8 fusion protein in the granulocytic maturation characteristic of the t(8;21) acute myelogenous leukemia revealed by microarray analysis. Shimada, H., Ichikawa, H., Ohki, M. Leukemia (2002) [Pubmed]
 
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