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

2012-01-01   Jean-Loup Huret 

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

Identity

HGNC
LOCATION
19p13.3
LOCUSID
ALIAS
AGM8,E2A,E47,ITF1,TCF-3,VDIR,bHLHb21,p75
FUSION GENES

DNA/RNA

Atlas Image

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

Atlas Image
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

Atlas Image
Atlas Image

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.

Bibliography

Pubmed IDLast YearTitleAuthors
173113192007Molecular cytogenetic characterization of TCF3 (E2A)/19p13.3 rearrangements in B-cell precursor acute lymphoblastic leukemia.Barber KE et al
100867271999Identification of a novel molecular partner of the E2A gene in childhood leukemia.Brambillasca F et al
75185491994E2A/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
81673431994Hairy cell leukemia is characterized by clonal chromosome abnormalities clustered to specific regions.Haglund U et al
15168261992Hlf, 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
86082071996Chromosomal translocations involving the E2A gene in acute lymphoblastic leukemia: clinical features and molecular pathogenesis.Hunger SP et al
13861621992Fusion of the leucine zipper gene HLF to the E2A gene in human acute B-lineage leukemia.Inaba T et al
97421201998The AD1 and AD2 transactivation domains of E2A are essential for the antiapoptotic activity of the chimeric oncoprotein E2A-HLF.Inukai T et al
159908652005CIZ gene rearrangements in acute leukemia: report of a diagnostic FISH assay and clinical features of nine patients.La Starza R et al
112370732001Multicolor spectral karyotyping identifies novel translocations in childhood acute lymphoblastic leukemia.Mathew S et al
20188381991New recurring chromosomal translocations in childhood acute lymphoblastic leukemia.Raimondi SC et al
118475182002Microsatellite instability and cytogenetic survey in myeloid leukemias.Ribeiro EM et al
176042082008E2A proteins: regulators of cell phenotype in normal physiology and disease.Slattery C et al
114174932001Expression 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
165312712006Characterization 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
181855222008E2A-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 IDTranscript IDUniprot
ENSG00000071564ENST00000262965P15923
ENSG00000071564ENST00000344749A0A0A0MRB7
ENSG00000071564ENST00000395423P15923
ENSG00000071564ENST00000453954X6REB3
ENSG00000071564ENST00000585731A0A0A0MTS0
ENSG00000071564ENST00000585855K7EK65
ENSG00000071564ENST00000586164K7EJN4
ENSG00000071564ENST00000586318K7ENI0
ENSG00000071564ENST00000586410K7EPH6
ENSG00000071564ENST00000587235K7ELF3
ENSG00000071564ENST00000587425K7EPS2
ENSG00000071564ENST00000588136P15923
ENSG00000071564ENST00000590436K7ENH8
ENSG00000071564ENST00000590684K7EMM4
ENSG00000071564ENST00000592395K7EJN4
ENSG00000071564ENST00000592628K7EKB9
ENSG00000071564ENST00000593064K7ERZ7
ENSG00000071564ENST00000611869P15923
ENSG00000071564ENST00000651991A0A494C1R3

Expression (GTEx)

0
50
100
150

Pathways

PathwaySourceExternal ID
HTLV-I infectionKEGGko05166
HTLV-I infectionKEGGhsa05166
Transcriptional misregulation in cancerKEGGko05202
Transcriptional misregulation in cancerKEGGhsa05202
Signaling pathways regulating pluripotency of stem cellsKEGGhsa04550
Signaling pathways regulating pluripotency of stem cellsKEGGko04550
Developmental BiologyREACTOMER-HSA-1266738
MyogenesisREACTOMER-HSA-525793
CDO in myogenesisREACTOMER-HSA-375170

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
183907092008Aging down-regulates the transcription factor E2A, activation-induced cytidine deaminase, and Ig class switch in human B cells.103
212584092011miR-495 is upregulated by E12/E47 in breast cancer stem cells, and promotes oncogenesis and hypoxia resistance via downregulation of E-cadherin and REDD1.80
153338392004E protein silencing by the leukemogenic AML1-ETO fusion protein.77
167828102006Gene expression patterns define novel roles for E47 in cell cycle progression, cytokine-mediated signaling, and T lineage development.74
238125882013A stable transcription factor complex nucleated by oligomeric AML1-ETO controls leukaemogenesis.49
238125882013A stable transcription factor complex nucleated by oligomeric AML1-ETO controls leukaemogenesis.49
192995592009MyoD and E-protein heterodimers switch rhabdomyosarcoma cells from an arrested myoblast phase to a differentiated state.43
262145922015Genomics and drug profiling of fatal TCF3-HLF-positive acute lymphoblastic leukemia identifies recurrent mutation patterns and therapeutic options.43
218282742011HEB and E2A function as SMAD/FOXH1 cofactors.37
151382692004Regulation of cellular senescence and p16(INK4a) expression by Id1 and E47 proteins in human diploid fibroblast.31

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

Historical Card

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

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