TCF3 (transcription factor 3 (E2A immunoglobulin enhancer binding factors E12/E47))

2012-01-01 Jean-Loup Huret Affiliation

Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France

Identity

HGNC

TCF3

LOCATION

19p13.3

LOCUSID

6929

ALIAS

AGM8,E2A,E47,ITF1,TCF-3,VDIR,bHLHb21,p75

FUSION GENES

Show Gene Fusions

DNA/RNA

Description

The E2A gene encodes two distinct basic helix-loop-helix transcription factors, E12 (ITF1) and E47 (TCF3) through alternative splicing.

Transcription

4,4 kb mRNA; coding sequence: 2,0 kb; alternate splicing --> E12 and E47, having different bHLH encoding exons (+ also E2-5).

Proteins

TCF3 (19p13.3) protein and domains.

Description

It forms homodimers and heterodimers with other basic helix-loop-helix transcription factors, such as ASCL1, MYOD1, TAL1, MYOG, NEUROG1, and TWIST1. It contains a transactivation domain (ADI) in N-term, a nuclear localization signal, activation domain II (ADII) (antiapoptotic), an ubiquitin ligase domain, a DNA binding motif, and a helix-loop-helix motif which mediates protein dimerisation in C-term.

Expression

Widely expressed.

Localisation

Nuclear.

Function

Ubiquitously expressed during development and in areas of rapid cell proliferation and differentiation. Role in cell growth, cell commitment, and differentiation. Role in epithelial mesenchymal transition. During epithelial mesenchymal transition, TGF-beta upregulates E2A proteins. E2A proteins are down regulated by the ubiquitin pathway (review in Slattery et al., 2008). Essential for normal B-cell hematopoiesis.

Homology

With other proteins with a helix-loop-helix dimerization domain signature, MYC type (MYC family, of which are MYC, LYL1, TAL1).

Implicated in

Entity name

t(1;19)(q23;p13)/B-ALL --> hybrid gene: TCF3/PBX1

Disease

pre B-ALL mainly; CD19+, CD10+, CD9+ (review in Hunger, 1996).

Prognosis

Controversial data; associated with poor prognostic features.

Cytogenetics

Two different forms:
- the balanced t(1;19);
- the unbalanced form, with 2 normal chromosomes 1, a der(19), and a normal chromosome19: --> partial trisomy for 1q23-1qter and monosomy for 19p13.3-pter;
additional anomalies: in half of the cases; they are various.

Hybrid gene

5 TCF3 - 3 PBX1; breakpoints are clustered on both genes.

Fusion protein

N-term transcriptional activation domains from TCF3 fused to the Hox cooperative motif and homeodomain of C-term PBX1.

Oncogenesis

Potent transcriptional activator; pleiotropic transforming activity.

Entity name

t(12;19)(p13;p13)/B-ALL --> hybrid gene: TCF3/ZNF384

Disease

Pro-B acute lymphoblastic leukemia with expression of myeloid antigens (La Starza et al., 2005; Zhong et al., 2008).

Prognosis

Relatively good prognosis.

Cytogenetics

The t(12;19)(p13;p13) is cryptic.

Hybrid gene

5 TCF3 - 3 ZNF384

Entity name

t(13;19)(q14;p13)

Disease

Only one case to date, an adult patient with pre B-ALL; she achieved complete remission (Barber et al., 2007).

Hybrid gene

The translocation involves TCF3 and an unknown partner in 13q14.

Entity name

t(17;19)(q22;p13)/B-ALL --> hybrid gene: TCF3 /HLF

Disease

Childhood B-ALL (Raimondi et al., 1991; Hunger et al., 1992; Inaba et al., 1992; Devaraj et al., 1994; Mathew et al., 2001; Takahashi et al., 2001; Ribeiro et al., 2002; Yeung et al., 2006; Barber et al., 2007).

Prognosis

Poor prognosis is likely.

Hybrid gene

5 TCF3 - 3 HLF

Fusion protein

N-term transcriptional activation domains from TCF3 fused to the basic leucine zipper from HLF C-term.

Oncogenesis

TCF3/HLF homodimers bind to promoter/enhancer elements of downstream target genes.

Entity name

t(19;19)(p13;q13)/B-ALL --> hybrid gene: TCF3 /TFPT

Disease

Childhood pre-B cell acute lymphoblastic leukemia (Brambillasca et al., 1999).

Cytogenetics

This chromosome rearrangement is cryptic.

Hybrid gene

5 TCF3 - 3 TFPT

Fusion protein

Retains the transactivation domain of TCF3, but with a truncation in TFPT, due to the frequent occurrence of a stop codon.

Breakpoints

Note

Breakpoints: 1- in t(1;19): are located (and dispersed) in the intron 13, and remove the bHLH domain; 2- in t(17;19) type I: are so far located at a given nucleotide in intron 13; in t(17;19) type II: are located in intron 12.

Article Bibliography

Pubmed ID	Last Year	Title	Authors
17311319	2007	Molecular cytogenetic characterization of TCF3 (E2A)/19p13.3 rearrangements in B-cell precursor acute lymphoblastic leukemia.	Barber KE et al
10086727	1999	Identification of a novel molecular partner of the E2A gene in childhood leukemia.	Brambillasca F et al
7518549	1994	E2A/HLF fusion cDNAs and the use of RT-PCR for the detection of minimal residual disease in t(17;19)(q22;p13) acute lymphoblastic leukemia.	Devaraj PE et al
8167343	1994	Hairy cell leukemia is characterized by clonal chromosome abnormalities clustered to specific regions.	Haglund U et al
1516826	1992	Hlf, a novel hepatic bZIP protein, shows altered DNA-binding properties following fusion to E2A in t(17;19) acute lymphoblastic leukemia.	Hunger SP et al
8608207	1996	Chromosomal translocations involving the E2A gene in acute lymphoblastic leukemia: clinical features and molecular pathogenesis.	Hunger SP et al
1386162	1992	Fusion of the leucine zipper gene HLF to the E2A gene in human acute B-lineage leukemia.	Inaba T et al
9742120	1998	The AD1 and AD2 transactivation domains of E2A are essential for the antiapoptotic activity of the chimeric oncoprotein E2A-HLF.	Inukai T et al
15990865	2005	CIZ gene rearrangements in acute leukemia: report of a diagnostic FISH assay and clinical features of nine patients.	La Starza R et al
11237073	2001	Multicolor spectral karyotyping identifies novel translocations in childhood acute lymphoblastic leukemia.	Mathew S et al
2018838	1991	New recurring chromosomal translocations in childhood acute lymphoblastic leukemia.	Raimondi SC et al
11847518	2002	Microsatellite instability and cytogenetic survey in myeloid leukemias.	Ribeiro EM et al
17604208	2008	E2A proteins: regulators of cell phenotype in normal physiology and disease.	Slattery C et al
11417493	2001	Expression of two types of E2A-HLF fusion proteins in YCUB-2, a novel cell line established from B-lineage leukemia with t(17;19).	Takahashi H et al
16531271	2006	Characterization of the t(17;19) translocation by gene-specific fluorescent in situ hybridization-based cytogenetics and detection of the E2A-HLF fusion transcript and protein in patients' cells.	Yeung J et al
18185522	2008	E2A-ZNF384 and NOL1-E2A fusion created by a cryptic t(12;19)(p13.3; p13.3) in acute leukemia.	Zhong CH et al

Other Information

Locus ID:

NCBI: 6929
MIM: 147141
HGNC: 11633
Ensembl: ENSG00000071564

Variants:

dbSNP: 6929
ClinVar: 6929
TCGA: ENSG00000071564
COSMIC: TCF3

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000071564	ENST00000262965	P15923
ENSG00000071564	ENST00000344749	A0A0A0MRB7
ENSG00000071564	ENST00000395423	P15923
ENSG00000071564	ENST00000453954	X6REB3
ENSG00000071564	ENST00000585731	A0A0A0MTS0
ENSG00000071564	ENST00000585855	K7EK65
ENSG00000071564	ENST00000586164	K7EJN4
ENSG00000071564	ENST00000586318	K7ENI0
ENSG00000071564	ENST00000586410	K7EPH6
ENSG00000071564	ENST00000587235	K7ELF3
ENSG00000071564	ENST00000587425	K7EPS2
ENSG00000071564	ENST00000588136	P15923
ENSG00000071564	ENST00000590436	K7ENH8
ENSG00000071564	ENST00000590684	K7EMM4
ENSG00000071564	ENST00000592395	K7EJN4
ENSG00000071564	ENST00000592628	K7EKB9
ENSG00000071564	ENST00000593064	K7ERZ7
ENSG00000071564	ENST00000611869	P15923
ENSG00000071564	ENST00000651991	A0A494C1R3

Expression (GTEx)

100

150

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
HTLV-I infection	KEGG	ko05166
HTLV-I infection	KEGG	hsa05166
Transcriptional misregulation in cancer	KEGG	ko05202
Transcriptional misregulation in cancer	KEGG	hsa05202
Signaling pathways regulating pluripotency of stem cells	KEGG	hsa04550
Signaling pathways regulating pluripotency of stem cells	KEGG	ko04550
Developmental Biology	REACTOME	R-HSA-1266738
Myogenesis	REACTOME	R-HSA-525793
CDO in myogenesis	REACTOME	R-HSA-375170

Protein levels (Protein atlas)

Not detected

Low

Medium

High

References

Pubmed ID	Year	Title	Citations
37129918	2024	Rare TCF3 variants associated with pediatric B cell acute lymphoblastic leukemia.	0
38303515	2024	Transcription factor 3 is dysregulated in megakaryocytes in myelofibrosis.	1
37129918	2024	Rare TCF3 variants associated with pediatric B cell acute lymphoblastic leukemia.	0
38303515	2024	Transcription factor 3 is dysregulated in megakaryocytes in myelofibrosis.	1
36460773	2023	FBXL2 promotes E47 protein instability to inhibit breast cancer stemness and paclitaxel resistance.	4
36576946	2023	Identification of TCF3 germline variants in pediatric B-cell acute lymphoblastic leukemia.	4
37000263	2023	Exportin XPO7 acts as an oncogenic factor in prostate cancer via upregulation of TCF3.	0
37277074	2023	TCF3 haploinsufficiency defined by immune, clinical, gene-dosage, and murine studies.	1
37607071	2023	Transcription factor 3 promotes migration and invasion potential and maintains cancer stemness by activating ID1 expression in esophageal squamous cell carcinoma.	0
37704696	2023	Molecular characterization of TCF3::PBX1 chromosomal breakpoints in acute lymphoblastic leukemia and their use for measurable residual disease assessment.	2
37721971	2023	Transcription Factor TCF3 Promotes Macrophage-Mediated Inflammation and MMP Secretion in Abdominal Aortic Aneurysm by Regulating miR-143-5p /CCL20.	0
38047107	2023	E47 as a novel glucocorticoid-dependent gene mediating lipid metabolism in patients with endogenous glucocorticoid excess.	0
36460773	2023	FBXL2 promotes E47 protein instability to inhibit breast cancer stemness and paclitaxel resistance.	4
36576946	2023	Identification of TCF3 germline variants in pediatric B-cell acute lymphoblastic leukemia.	4
37000263	2023	Exportin XPO7 acts as an oncogenic factor in prostate cancer via upregulation of TCF3.	0

Citation

Jean-Loup Huret

TCF3 (transcription factor 3 (E2A immunoglobulin enhancer binding factors E12/E47))

Atlas Genet Cytogenet Oncol Haematol. 2012-01-01

Online version: http://atlasgeneticsoncology.org/gene/50/tcf3-(transcription-factor-3-(e2a-immunoglobulin-enhancer-binding-factors-e12-e47))

Historical Card

1997-12-01 TCF3 (transcription factor 3 (E2A immunoglobulin enhancer binding factors E12/E47)) by Jean-Loup Huret Affiliation

Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France