CBFA2T3 (core-binding factor, runt domain, alpha subunit 2; translocated to, 3)
2005-10-01 Anthony J Bais AffiliationDepartment of Haematology, Genetic Pathology, Flinders University, Bedford Park, Adelaide, SA 5042, Australia
Identity
HGNC
LOCATION
16q24.3
LOCUSID
ALIAS
ETO2,MTG16,MTGR2,RUNX1T3,ZMYND4
FUSION GENES
DNA/RNA
Description
CBFA2T3 encodes two alternative transcripts, CBFA2T3A and CBFA2T3B, via the use of alternative start sites at exons 1A and 1B, respectively.
CBFA2T3A is 4,265-bp in length, composed of 13 exons (1A and 2 to 12) spanning approximately 130-kb of genomic DNA, and has an ORF of 1,959-bp encoding a protein of 653 amino acids.
CBFA2T3B is 4,034-bp in length, composed of 12 exons (1B to 12 splicing out exon 3) spanning approximately 50-kb of genomic DNA, and has an ORF of 1,701-bp encoding a protein of 567 amino acids.
Additional CBFA2T3C and CBFA2T3D isoforms have been identified in leukemic and HEL cell lines. CBFA2T3C encodes a protein that lacks exons 2 and 3, and CBFA2T3D is a truncated protein with out-of-frame splicing of exon 1A to exon 5.
The CBFA2T3A open-reading-frame (ORF) may include an additional 177 amino acids beyond the originally proposed methionine start codon.
The CBFA2T3B isoform contains a high-density 1-kb CpG island within and five prime to the exon 1B start site.
A hypothetical protein FLJ26728 located within and proximal to the CpG island transcribes antisense to CBFA2T3. Another hypothetical protein FLJ23429 transcribes antisense starting from within the first alternative intron.
Pseudogene
None identified.
Proteins
Description
ETO proteins are composed of four evolutionarily conserved domains termed nervy homology regions (NHR1 to 4) and three proline-serine-threonine (PST) rich regions. The fourth NHR region is also referred to as the zinc-finger MYND (zf myeloid-nervy-DEAF-1) domain.
NHR1 shares significant homology to human TATA-binding protein (TBP)-associated factor 130 (hTAF 130), hTAF 105, Drosophila accessory or activation factor TAF 110, and is often referred to as the TAF 110 domain.
NHR2 is a small region containing homo and heterodimerization domains and a hydrophobic heptad repeat (HHR) unit.
The sequence of NHR3 is unremarkable in homology and often referred to as the nervy domain.
The C-terminal NHR4 domain exists in numerous human, murine, Caenorhabditis elegans and Drosophila proteins, and contains a MYND zinc-finger motif. The motif is composed of CXXC and two (C-H)XXXC regions which correspond to cysteine-histidine knuckle structures that are the basic building blocks of many zinc-finger proteins. The zinc-finger is common to the developmental proteins rat programmed cell death (RP-8), the human homolog programmed cell death 2 (PDCD2), deformed epidermal autoregulatory factor-1 (DEAF-1), suppressin (SPN), BLU or zinc-finger MYND domain containing 10 (ZMYND10), adenovirus 5 E1A binding protein (BS69), and CD8 beta opposite (BOP).
Expression
CBFA2T3 is widely expressed in B-cells, blood, brain, breast, cervix, colon, eye, kidney tumor, lymph, marrow, muscle, pancreas, placenta and tonsil. CBFA2T3 exists predominantly as 4.5 and 4.2-kb transcripts along with several other minor RNAs in heart, brain, placenta, lung, liver, skeletal muscle, kidney, pancreas, spleen, thymus, prostate, testis, ovary, small intestine, colon and peripheral blood leukocyte.
Localisation
All ETO members contain nuclear localization signals (NLS), some of which may be abrogated through five prime variations to enable extracellular targeting. For instance, CBFA2T1 has been detected in the cytoplasm of Purkinje cells in adult human brain, and both CBFA2T1 and CBFA2T3B have been detected in the Golgi apparatus, where they may function as cAMP-dependent protein kinase anchoring proteins. The majority of ETO proteins presumably remain in the nucleus for transcriptional regulation.
Function
CBFA2T3 has been considered to function as a transcriptional repressor via interaction with corepressor complexes.
The CBFA2T3A isoform oligomerizes and drags MTG8 and MTGR1 to the nucleus, oligomerizes with RUNX1-MTG16 fusion proteins in the nucleoplasm, interacts with nuclear HDACs 1 and 3, and when overexpressed accumulates at the periphery of nucleoli in characteristic rings. Because clustered arrays of inactive methylated ribosomal DNA (rDNA) repeats are also found at the nucleoli periphery, it has been speculated that CBFAT23A could be involved in methylation silencing of rDNA in the nucleolus.
The CBFA2T3B isoform has been shown to function in T lymphocytes as a kinase anchorage protein, and interact with cyclic nucleotide phosphodiesterases, suggesting it may function in T cell activation and inflammatory response. CBFA2T3B has been shown to function as a transcriptional repressor when tethered to a GAL4 DNA-binding domain in gene reporter assays, and inhibit the growth of breast tumor cell lines with reduced expression when ectopically expressed using retrovirus.
CBFA2T3 has been found to interact with a novel zinc finger protein KIA00924 to mediate potent transcriptional repression as determined by CAT reporter gene assays. The presence of a zinc-finger motif common to developmental proteins suggests that CBFA2T3 might function in regulating differentiation and morphogenesis. The RP-8 and human homolog PDCD2 proteins assume a role in programmed cell death, a process essential for epithelial turnover. DEAF-1 is essential for early embryonic dorsal epidermal, eye and wing development in Drosophila. BOP encodes a muscle-restricted protein essential for cardiomyocyte differentiation and morphogenesis. BLU is a candidate tumor suppressor gene from the 3p21.3 LOH region in many human cancers, and SPN from rat functions as a potent tumor suppressor of leukemia, lymphoma and thymoma cells and tumor cells from the brain, breast, pituitary and adrenal glands.
CBFA2T3 transcripts of CD34(+) progenitor cells have been shown to be rapidly reduced by cytokine-induced differentiation into myeloid or erythroid lineages, supporting suggestion that CBFA2T3 may function in hematopoietic differentiation. The CBFA2T3B CpG island contains several Specificity protein 1 (Sp1), homeotic, epidermal and insulin growth factor recognition sites. High conserved binding sites include GATA-1, CREB, F-1 and PKNOX1.
Homology
The human gene CBFA2T3 is a member of the eight-twenty-one (ETO) family of proteins. The human ETO family consists of the ETO gene, also known as the myeloid translocation gene 8 (MTG8, CBFA2T1), the myeloid translocation gene related protein-1 (EHT, MTGR1, CBFA2T2), and the myeloid translocation gene 16 (MTG16, MTGR2, ZMYND4, HGNC:1537, CBFA2T3).
Murine homologs of the ETO family include mETO (cbfa2t1h), ET0-2 (cbfa2t3h), and cbfa2t2h, the latter of which is uncharacterised. Chicken cETO and Drosophila nervy homologs have also been identified.
The ETO protein family members and NHRs are highly homologous and conserved to each other. The CBFA2T3A and B isoforms share significant homology to MTG8 (67 and 75%, respectively) and MTGR1 (54 and 61%, respectively), and approximately 30% homology to nervy. CBFA2T3 shares 86% homology to the murine ETO-2 (cbfa2t3h), which in turn shares 75 and 60% homology to MTG8 and MTGR1, respectively, suggesting that ETO-2 is the murine homolog of CBFA2T3. MTG8 is approximately 99, 65 and 30% homologous to murine ETO, MTGR1 and nervy, respectively.
Murine homologs of the ETO family include mETO (cbfa2t1h), ET0-2 (cbfa2t3h), and cbfa2t2h, the latter of which is uncharacterised. Chicken cETO and Drosophila nervy homologs have also been identified.
The ETO protein family members and NHRs are highly homologous and conserved to each other. The CBFA2T3A and B isoforms share significant homology to MTG8 (67 and 75%, respectively) and MTGR1 (54 and 61%, respectively), and approximately 30% homology to nervy. CBFA2T3 shares 86% homology to the murine ETO-2 (cbfa2t3h), which in turn shares 75 and 60% homology to MTG8 and MTGR1, respectively, suggesting that ETO-2 is the murine homolog of CBFA2T3. MTG8 is approximately 99, 65 and 30% homologous to murine ETO, MTGR1 and nervy, respectively.
Mutations
Note
None recorded.
Implicated in
Entity name
Note
CBFA2T3 or MTG16 was identified by molecular characterization of a second less common therapy-related AML translocation involving t(16;21). Characterization of the t(16;21) demonstrated that RUNX1-MTG16 fusion transcripts similar to RUNX1-ETO were generated
Fusion protein
Entity name
Loss of heterozygosity (LOH) of 16q22-qter in breast cancer, prostate cancer, and several other cancers
Note
This region is frequently deleted in several human cancers causing loss of heterozygosity. The 16q24.3 region including CBFA2T3 spans approximately 3-Mb from the marker D16S498 to the telomere and contains at least two smallest regions of overlap (SROs). These SROs are most frequently deleted in early and late stage breast cancer and in prostate cancer. Loss of normal function of CBFA2T3 may be a key event in the early stage of breast cancer. LOH on the whole 16q22-qter region is frequently detected in breast and prostate cancer.
CBFA2T3B is a potential tumor suppressor gene affected by LOH, aberrant gene expression and promoter methylation in breast cancer. Quantitative gene expression analysis of 78 genes in the 16q24.3 region demonstrated that CBFA2T3 was the only gene with an aberrant expression profile distinctly similar to the known tumor suppressors SYK and CDKN2A. 68 genes displayed normal expression, six displayed mildly aberrant expression (DPEP1, CDH15, Hs.17074, Hs.189419, SLC7A5 and AA994450), one displayed excessively reduced expression (CA5A), and two displayed moderately aberrant expression (CYBA and FBX031). The CBFA2T3B promoter region displays aberrant hypo and hypermethylation in breast tumor cell lines and primary breast tumor samples in correlation with aberrant gene expression.
CBFA2T3B is a potential tumor suppressor gene affected by LOH, aberrant gene expression and promoter methylation in breast cancer. Quantitative gene expression analysis of 78 genes in the 16q24.3 region demonstrated that CBFA2T3 was the only gene with an aberrant expression profile distinctly similar to the known tumor suppressors SYK and CDKN2A. 68 genes displayed normal expression, six displayed mildly aberrant expression (DPEP1, CDH15, Hs.17074, Hs.189419, SLC7A5 and AA994450), one displayed excessively reduced expression (CA5A), and two displayed moderately aberrant expression (CYBA and FBX031). The CBFA2T3B promoter region displays aberrant hypo and hypermethylation in breast tumor cell lines and primary breast tumor samples in correlation with aberrant gene expression.
Disease
16q22-qter LOH is detected in bilateral breast cancer and ductal lavage, in rare inflammatory breast cancer, and in several other cancers, including central nervous system neuroectodermal and primary ependymomas, colorectal liver metastases, gastric tumor, head and neck squamous cell carcinoma, hepatocellular carcinoma, lung tumor, nasopharyngeal tumor, ovarian tumor, rhabdomyosarcoma, and Wilms tumor. 16q22-qter LOH in ovarian, hepatocellular and particularly breast and prostate cancers, exhibit similar SROs, suggesting common molecular pathways are affected.
Article Bibliography
| Pubmed ID | Last Year | Title | Authors |
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Other Information
Locus ID:
NCBI: 863
MIM: 603870
HGNC: 1537
Ensembl: ENSG00000129993
Variants:
dbSNP: 863
ClinVar: 863
TCGA: ENSG00000129993
COSMIC: CBFA2T3
RNA/Proteins
Expression (GTEx)
Protein levels (Protein atlas)
References
| Pubmed ID | Year | Title | Citations |
|---|---|---|---|
| 38243303 | 2024 | CNS erythroblastic sarcoma: a potential emerging pediatric tumor type characterized by NFIA::RUNX1T1/3 fusions. | 0 |
| 38243303 | 2024 | CNS erythroblastic sarcoma: a potential emerging pediatric tumor type characterized by NFIA::RUNX1T1/3 fusions. | 0 |
| 32434928 | 2020 | The transcriptional corepressor CBFA2T3 inhibits all-trans-retinoic acid-induced myeloid gene expression and differentiation in acute myeloid leukemia. | 7 |
| 32960220 | 2020 | Embryonic erythropoiesis and hemoglobin switching require transcriptional repressor ETO2 to modulate chromatin organization. | 9 |
| 32434928 | 2020 | The transcriptional corepressor CBFA2T3 inhibits all-trans-retinoic acid-induced myeloid gene expression and differentiation in acute myeloid leukemia. | 7 |
| 32960220 | 2020 | Embryonic erythropoiesis and hemoglobin switching require transcriptional repressor ETO2 to modulate chromatin organization. | 9 |
| 30858547 | 2019 | Kaiso is required for MTG16-dependent effects on colitis-associated carcinoma. | 7 |
| 31040112 | 2019 | Myeloid translocation gene CBFA2T3 directs a relapse gene program and determines patient-specific outcomes in AML. | 12 |
| 31370031 | 2019 | Genome-wide association study identifies CBFA2T3 affecting the rate of CSF Aβ(42) decline in non-demented elders. | 1 |
| 30858547 | 2019 | Kaiso is required for MTG16-dependent effects on colitis-associated carcinoma. | 7 |
| 31040112 | 2019 | Myeloid translocation gene CBFA2T3 directs a relapse gene program and determines patient-specific outcomes in AML. | 12 |
| 31370031 | 2019 | Genome-wide association study identifies CBFA2T3 affecting the rate of CSF Aβ(42) decline in non-demented elders. | 1 |
| 27572702 | 2017 | Med19 promotes breast cancer cell proliferation by regulating CBFA2T3/HEB expression. | 11 |
| 28292442 | 2017 | ETO2-GLIS2 Hijacks Transcriptional Complexes to Drive Cellular Identity and Self-Renewal in Pediatric Acute Megakaryoblastic Leukemia. | 41 |
| 27572702 | 2017 | Med19 promotes breast cancer cell proliferation by regulating CBFA2T3/HEB expression. | 11 |
Citation
Anthony J Bais
CBFA2T3 (core-binding factor, runt domain, alpha subunit 2; translocated to, 3)
Atlas Genet Cytogenet Oncol Haematol. 2005-10-01
Online version: http://atlasgeneticsoncology.org/gene/428/cbfa2t3
