Disease relevance of RUNX1T1

• The ETO protein disrupted in t(8;21)-associated acute myeloid leukemia is a corepressor for the promyelocytic leukemia zinc finger protein [1].
• Nearly 40% of cases of acute myelogenous leukemia (AML) of the M2 subtype are due to a chromosomal translocation that combines a sequence-specific DNA binding protein, AML1, with a potent transcriptional repressor, ETO [2].
• Cryptic chromosomal aberrations leading to an AML1/ETO rearrangement are frequently caused by small insertions [3].
• ETO protein of t(8;21) AML is a corepressor for Bcl-6 B-cell lymphoma oncoprotein [4].
• Therefore, ETO is a bona fide corepressor that links the transcriptional pathogenesis of acute leukemias and B-cell lymphomas and offers a compelling target for transcriptional therapy of hematologic malignancies [4].

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

• SMRT-N-CoR interaction requires each of two zinc fingers contained in C-terminal Nervy homology region 4 (NHR4) of ETO [2].
• We found that ETO is one of the corepressors recruited by PLZF [1].
• Corepression by ETO was completely abrogated by histone deacetylase inhibitors [1].
• The AML1-MTG8 leukemic fusion protein forms a complex with a novel member of the MTG8(ETO/CDR) family, MTGR1 [31].
• ETO and MTG16 are both part of fusion proteins resulting from chromosomal translocations associated with acute myeloid leukemia [19].
• Loss of p21(WAF1) facilitates AML1-ETO-induced leukemogenesis, suggesting that mutagenic events in the p21(WAF1) pathway to bypass the growth inhibitory effect from AML1-ETO-induced p21(WAF1) expression can be a significant factor in AML1-ETO-associated acute myeloid leukemia [32].
• AML1-ETO quickly shuts off scl expression, and restoration of scl expression rescues the effects of AML1-ETO on myeloerythroid progenitor cell fate [33].

Analytical, diagnostic and therapeutic context of RUNX1T1

• Molecular cloning of cDNA indicated that the AML1-MTG8-binding protein (MTGR1) is highly related to MTG8 and similar to Drosophila Nervy [31].
• The variant proteins of both MTG8 and AML1-MTG8 reduced transcriptional repressor activity in a mammalian two-hybrid assay [17].
• 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 [34].
• Immunoprecipitations of metabolically labeled 32P-proteins from Kasumi-1 cells show that AML1 and ETO are phosphorylated on serine and threonine [21].
• Indirect immunofluorescence microscopy showed that MTG8 and RIIalpha were overlapped at the centrosome-Golgi area in lymphocytes [24].

References