Gene Summary

Gene:TCF3; transcription factor 3
Aliases: E2A, E47, p75, AGM8, ITF1, VDIR, TCF-3, bHLHb21
Summary:This gene encodes a member of the E protein (class I) family of helix-loop-helix transcription factors. E proteins activate transcription by binding to regulatory E-box sequences on target genes as heterodimers or homodimers, and are inhibited by heterodimerization with inhibitor of DNA-binding (class IV) helix-loop-helix proteins. E proteins play a critical role in lymphopoiesis, and the encoded protein is required for B and T lymphocyte development. Deletion of this gene or diminished activity of the encoded protein may play a role in lymphoid malignancies. This gene is also involved in several chromosomal translocations that are associated with lymphoid malignancies including pre-B-cell acute lymphoblastic leukemia (t(1;19), with PBX1), childhood leukemia (t(19;19), with TFPT) and acute leukemia (t(12;19), with ZNF384). Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene, and a pseudogene of this gene is located on the short arm of chromosome 9. [provided by RefSeq, Sep 2011]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:transcription factor E2-alpha
Source:NCBIAccessed: 30 August, 2019


What does this gene/protein do?
Show (45)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 30 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Biomarkers, Tumor
  • Retinoic Acid
  • Burkitt Lymphoma
  • Trisomy
  • Cancer Gene Expression Regulation
  • Messenger RNA
  • Gene Expression
  • Chromosome 1
  • Breast Cancer
  • Core Binding Factor Alpha 2 Subunit
  • MicroRNAs
  • DNA-Binding Proteins
  • FISH
  • TCF3
  • High-Throughput Nucleotide Sequencing
  • B-Lymphocytes
  • Fusion Proteins, bcr-abl
  • Chromosome 19
  • Adolescents
  • Young Adult
  • Mutation
  • Tumor Necrosis Factor Receptor Superfamily, Member 7
  • Homeodomain Proteins
  • Taiwan
  • Survival Rate
  • Infant
  • Basic Helix-Loop-Helix Transcription Factors
  • Molecular Sequence Data
  • Acute Lymphocytic Leukaemia
  • Trans-Activators
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma
  • Proto-Oncogene Proteins
  • Colorectal Cancer
  • Oncogene Fusion Proteins
  • KMT2A
  • Gene Expression Profiling
  • Liver Cancer
  • Childhood Cancer
  • Cell Differentiation
  • Cell Proliferation
  • Disease-Free Survival
  • pbx1
  • Sudan
Tag cloud generated 30 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: TCF3 (cancer-related)

Tang E, Wang Y, Liu T, Yan B
Gastrin promotes angiogenesis by activating HIF-1α/β-catenin/VEGF signaling in gastric cancer.
Gene. 2019; 704:42-48 [PubMed] Related Publications
Angiogenesis is recognized as a sign of cancer and facilitates cancer progression and metastasis. Suppression of angiogenesis is a desirable strategy for gastric cancer (GC) management. In this study, we showed a novel role of gastrin in angiogenesis of GC. We observed that treatment with gastrin 17 (G17) increased the proliferation of AGS cells and enhanced tube formation during normoxia and hypoxia. The expression level of VEGF were increased by G17 treatment as well. Experiments on the mechanism showed that G17 promoted HIF-1α expression, which subsequently enhanced β-catenin nuclear localization and activation of TCF3 and LEF1 and finally resulted in angiogenesis by upregulating VEGF. An in vivo experiment confirmed that G17 enhanced GC cell proliferation and angiogenesis in the resultant tumor. In conclusion, our findings indicate that gastrin promotes angiogenesis via activating HIF-1α/β-catenin/VEGF axis in GC.

López C, Kleinheinz K, Aukema SM, et al.
Genomic and transcriptomic changes complement each other in the pathogenesis of sporadic Burkitt lymphoma.
Nat Commun. 2019; 10(1):1459 [PubMed] Free Access to Full Article Related Publications
Burkitt lymphoma (BL) is the most common B-cell lymphoma in children. Within the International Cancer Genome Consortium (ICGC), we performed whole genome and transcriptome sequencing of 39 sporadic BL. Here, we unravel interaction of structural, mutational, and transcriptional changes, which contribute to MYC oncogene dysregulation together with the pathognomonic IG-MYC translocation. Moreover, by mapping IGH translocation breakpoints, we provide evidence that the precursor of at least a subset of BL is a B-cell poised to express IGHA. We describe the landscape of mutations, structural variants, and mutational processes, and identified a series of driver genes in the pathogenesis of BL, which can be targeted by various mechanisms, including IG-non MYC translocations, germline and somatic mutations, fusion transcripts, and alternative splicing.

Park SH, You E, Park CJ, et al.
The Incidence and Immunophenotypic and Genetic Features of JL1 Expressing Cells and the Therapeutic Potential of an Anti-JL1 Antibody in
Ann Lab Med. 2019; 39(4):358-366 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: JL1 is a newly identified CD43 epitope that specifically recognizes leukemic cells. We analyzed the incidence of JL1 expression and compared the clinical, immunophenotypic, and genetic characteristics of
METHODS: Seventy-eight patients with pediatric acute leukemia (52 with ALL, 26 with AML) diagnosed between December 2014 and January 2016 were enrolled prospectively. Flow cytometry for JL1 expression was performed at diagnosis. Clinical, immunophenotypic, and genetic characteristics were compared with respect to JL1 expression status by the Student t-test/Mann-Whitney U test and chi-square test/Fisher's exact test.
RESULTS: The incidence of JL1 expression was 76.9% and 84.6% in ALL and AML patients, respectively. ALL patients with JL1 expression showed higher CD10 and cytoplasmic IgM expressions than those without JL1 expression (
CONCLUSIONS: Our findings support the potential therapeutic role of anti-JL1 monoclonal antibodies; JL1 expression was associated with specific immunophenotypes and genetic abnormalities. Future studies should examine the prognostic impact of JL1 expression in pediatric acute leukemias.

Piskunova IS, Obukhova TN, Parovichnikova EN, et al.
Structure and significance of cytogenetic abnormalities in adult patients with Ph-negative acute lymphoblastic leukemia.
Ter Arkh. 2018; 90(7):30-37 [PubMed] Related Publications
AIM: To evaluate occurrence, variety, structural peculiarities and prognostic meaning of cytogenetic abnormalities in adult patients with Ph-negative acute lymphoblastic leukemia (ALL) receiving therapy according to ALL-2009 protocol.
MATERIALS AND METHODS: The study included 115 adult patients with firstly diagnosed Ph-negative ALL: 58 male and 57 female aged from 15 to 61 years (mean age 26.5 years), who underwent treatment from September 2009 to September 2015 in National Medical Research Center for Hematology MH RF (n=101) and in hematology departments of regional hospitals (n=14). All patients received therapy of ALL-2009 protocol (, NCT01193933). The median follow-up was 24.5 months (0.2-94.4 months). As a part of the study results of a standard cytogenetic assay (SCA) were analyzed and fluorescence hybridization in situ (FISH) with the use of DNA-probes was performed on archived biological material for structural changes in gene locuses MLL/t(11q23), с-MYC/t(8q24), TP53/ deletion 17p13, CDKN2A/ deletion 9p21, translocation t(1;19)/E2A-PBX1 и t(12;21)/ETV6-RUNX1; iAMP21 identification.
RESULTS: Karyotype was defined using SCA in 86% of patients. Normal karyotype was found in 48.5% of them, chromosome aberrations in 51.5% (structural changes were found in 19.2%, hyperploidy in 27.2%, and hypoploidy in 5.1%). In 17.2% of patients complex karyotype abnormalities were found. With the use of FISH technique aberrations were found in 67% of patients: 9p21/CDKN2A deletion in 24.3%, MLL/t(11q23) gene abnormalities in 7.8%, 17p13/TP53 deletion in 5.2%, abnormalities of c-MYC/t(8q24) in 1.7%, t(1;19)/E2A-PBX1 in 0.8%, and iAMP21 in 0.8%, other abnormalities (additional signals/absence of signals from gene locuses) in 26.4%, t(12;21)/ETV6-RUNX1 was not found. FISH technique use in addition to SCA allows to increase aberrant karyotype location from 51.5 to 67%. A statistically significant correlation of 9p21/CDKN2A deletion with high serum lactate dehydrogenase activity (p=0.02); MLL/t(11q23) gene abnormalities - with leucocytosis and high blast cells level in blood (p=0.0016), hyperploidy - with normal leukocyte count (p=0.02) was shown. In groups with different cytogenetic abnormalities no statistically significant differences of treatment with ALL-2009 protocol were found (in terms of complete remission, early mortality and treatment resistance). When connection of cytogenetic abnormalities and their combinations with long-term results were analyzed according to ALL-2009 protocol, only two characteristics - MLL/t(11q23) and c MYC/t(8q24) gene abnormalities had a statistically significant influence on disease-free survival (HR - 176.9; p<0.0001) and chance of recurrence (HR - 6.4; p=0.02).
CONCLUSION: Adverse prognostic factors in terms of therapeutic management provided in ALL-2009 protocol were MLL/t(11q23) and с-MYC/t(8q24) genes abnormalities. CDKN2A/9p21 and TP53/17p13 genes deletions, quantative and complex karyotype abnormalities were not prognostic factors in adult patients with Ph-negative ALL in ALL-2009 protocol use.

Karvonen H, Perttilä R, Niininen W, et al.
Wnt5a and ROR1 activate non-canonical Wnt signaling via RhoA in TCF3-PBX1 acute lymphoblastic leukemia and highlight new treatment strategies via Bcl-2 co-targeting.
Oncogene. 2019; 38(17):3288-3300 [PubMed] Related Publications
B-cell precursor acute lymphoblastic leukemia (BCP-ALL) with TCF3-PBX1 fusion gene expression has constitutively elevated levels of Wnt16b and ROR1 (receptor tyrosine kinase-like orphan receptor), a ligand and a receptor from the Wnt signaling pathway, respectively. Although survival rate is usually high after the initial chemotherapy, many TCF3-PBX1 BCP-ALL patients relapse and subsequently develop treatment resistance, resulting in poor prognosis. Here, we aimed to investigate the molecular signaling associated with Wnt16b and ROR1 overexpression in TCF3-PBX1 cell lines and primary samples, and to identify effective treatment options via ROR1 targeting. We detected higher ROR1 expression on TCF3-PBX1 leukemic cells even at a later stage of patient relapse, providing a strong rationale for the use of ROR1-targeted therapy. We found that Wnt5a-ROR1 signaling enhances proliferation of TCF3-PBX1 cells via RhoA/Rac1 GTPases activation and STAT3 upregulation. Wnt16b also activated the RhoA/Rac1 signaling cascade suggesting the activation of a non-canonical Wnt pathway in TCF3-PBX1 cells. Wnt16 could interact with ROR1 but not in TCF3-PBX1 cells, suggesting that Wnt5a is the ligand signaling via ROR1 in TCF3-PBX1 cells. By high throughput drug-sensitivity testing of TCF3-PBX1 cells before and after ROR1 knockdown we found that targeting ROR1 significantly improves the therapeutic efficacy of Bcl-2 family inhibitors venetoclax and navitoclax, and this synergism was confirmed ex vivo using a drug-resistant primary sample from a relapsed TCF3-PBX1 patient. Our work underlines a new type of targeted combination therapy that could be clinically advantageous for patients with TCF3-PBX1 BCP-ALL.

Zheng L, Hu N, Zhou X
TCF3-activated LINC00152 exerts oncogenic role in osteosarcoma through regulating miR-1182/CDK14 axis.
Pathol Res Pract. 2019; 215(2):373-380 [PubMed] Related Publications
Long noncoding RNAs (lncRNAs) have been reported to participate in tumorigenesis and diverse cellular processes in osteosarcoma (OS). However, the role of lncRNA LINC00152 in OS remains elusive. In this study, LINC00152 was highly expressed in osteosarcoma tissues and cell lines. Moreover, MTT and colony formation assays revealed that knockdown of LINC00152 significantly suppressed cell proliferation. The inhibitory effect of LINC00152 knockdown on OS cell migration and invasion was analyzed and demonstrated by transwell assays. Additionally, Chromatin immunoprecipitation (ChIP) and luciferase reporter assays suggested that LINC00152 was transcriptionally activated by the transcription factor TCF3. More importantly, mechanism investigation revealed that LINC00152 was predominantly located in the cytoplasm of OS cells and acted as a competing endogenous RNA (ceRNA) in OS by regulating miR-1182/CDK14 axis. Collectively, LINC00152 was activated by TCF3 and promotes cell proliferation and migration in osteosarcoma via miR-1182-CDK14 axis.

Liu N, Song J, Xie Y, et al.
Different roles of E proteins in t(8;21) leukemia: E2-2 compromises the function of AETFC and negatively regulates leukemogenesis.
Proc Natl Acad Sci U S A. 2019; 116(3):890-899 [PubMed] Free Access to Full Article Related Publications
The AML1-ETO fusion protein, generated by the t(8;21) chromosomal translocation, is causally involved in nearly 20% of acute myeloid leukemia (AML) cases. In leukemic cells, AML1-ETO resides in and functions through a stable protein complex, AML1-ETO-containing transcription factor complex (AETFC), that contains multiple transcription (co)factors. Among these AETFC components, HEB and E2A, two members of the ubiquitously expressed E proteins, directly interact with AML1-ETO, confer new DNA-binding capacity to AETFC, and are essential for leukemogenesis. However, the third E protein, E2-2, is specifically silenced in AML1-ETO-expressing leukemic cells, suggesting E2-2 as a negative factor of leukemogenesis. Indeed, ectopic expression of E2-2 selectively inhibits the growth of AML1-ETO-expressing leukemic cells, and this inhibition requires the bHLH DNA-binding domain. RNA-seq and ChIP-seq analyses reveal that, despite some overlap, the three E proteins differentially regulate many target genes. In particular, studies show that E2-2 both redistributes AETFC to, and activates, some genes associated with dendritic cell differentiation and represses MYC target genes. In AML patients, the expression of E2-2 is relatively lower in the t(8;21) subtype, and an E2-2 target gene,

Barbosa TC, Lopes BA, Blunck CB, et al.
A novel PAX5 rearrangement in TCF3-PBX1 acute lymphoblastic leukemia: a case report.
BMC Med Genomics. 2018; 11(1):122 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Chromosome translocations are a hallmark of B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Additional genomic aberrations are also crucial in both BCP-ALL leukemogenesis and treatment management. Herein, we report the phenotypic and molecular cytogenetic characterization of an extremely rare case of BCP-ALL harboring two concomitant leukemia-associated chromosome translocations: t(1;19)(q23;q13.3) and t(9;17)(p13;q11.2). Of note, we described a new rearrangement between exon 6 of PAX5 and a 17q11.2 region, where intron 3 of SPECC1 is located. This rearrangement seems to disrupt PAX5 similarly to a PAX5 deletion. Furthermore, a distinct karyotype between diagnosis and relapse samples was observed, disclosing a complex clonal evolution during leukemia progression.
CASE PRESENTATION: A 16-year-old boy was admitted febrile with abdominal and joint pain. At clinical investigation, he presented with anemia, splenomegaly, low white blood cell count and 92% lymphoblast. He was diagnosed with pre-B ALL and treated according to high risk GBTLI-ALL2009. Twelve months after complete remission, he developed a relapse in consequence of a high central nervous system and bone marrow infiltration, and unfortunately died.
CONCLUSIONS: To our knowledge, this is the first report of a rearrangement between PAX5 and SPECC1. The presence of TCF3-PBX1 and PAX5-rearrangement at diagnosis and relapse indicates that both might have participated in the malignant transformation disease maintenance and dismal outcome.

Li JF, Dai YT, Lilljebjörn H, et al.
Transcriptional landscape of B cell precursor acute lymphoblastic leukemia based on an international study of 1,223 cases.
Proc Natl Acad Sci U S A. 2018; 115(50):E11711-E11720 [PubMed] Free Access to Full Article Related Publications
Most B cell precursor acute lymphoblastic leukemia (BCP ALL) can be classified into known major genetic subtypes, while a substantial proportion of BCP ALL remains poorly characterized in relation to its underlying genomic abnormalities. We therefore initiated a large-scale international study to reanalyze and delineate the transcriptome landscape of 1,223 BCP ALL cases using RNA sequencing. Fourteen BCP ALL gene expression subgroups (G1 to G14) were identified. Apart from extending eight previously described subgroups (G1 to G8 associated with

Singh M, Bhatia P, Shandilya JK, et al.
Low Expression of Leucocyte Associated Immunoglobulin Like Receptor-1 (LAIR-1/CD305) in a Cohort of Pediatric Acute Lymphoblastic Leukemia Cases
Asian Pac J Cancer Prev. 2018; 19(11):3131-3135 [PubMed] Free Access to Full Article Related Publications
Background: Immunophenotypic markers can play significant role in prognostic assessment for different cancers and leukocyte-associated Ig-like receptor (LAIR-1) is a recently identified inhibitory immuno-receptor. Methods: We measured LAIR-1 expression in paediatric ALL patients (n-42) and appropriate controls by flow cytometry. Median fluorescence intensities (MFIs) were calculated and correlated with demographic and clinical variables and early treatment outcome parameters. Results: The ALL cohort had an age range of 1 - 11 y and a M:F ratio of 2.5:1. 64% had WBC counts <50 x 109/L and 15 (36%) >50 x 109/L, 52% being standard risk and 48% high risk. There were 6 cases of T-ALL and 36 of B-ALL. AML1-TEL, E2A-PBX, BCR-ABL and MLL-AF4 transcripts were noted in 3, 6, 2 and 1 patient, respectively. Day 8 ABC was <1,000 in 31 and >1,000 in 8 cases, while 30 had low and 7 high MRD (both >0.01) at day 35 of treatment. The median MFI for LAIR-1 expression in control cases was 8.2 (range 7.76-11.69) and in ALL cases 4.02 (range 0.56 to 11.87), with 74% (n-31) of ALL cases showing reduced LAIR-1 expression. However, no significant correlations were found between standard ALL risk factors and LAIR-1 expression. Out of 42 patients, 4 died during induction treatment and one exited therapy, 60% (n-3/5) of these featuring low expression of LAIR-1. Also ALL patients with low LAIR-1 expression had t (12;21), t (1;19) and t (4;11) translocations in 2, 4 and 1 samples, respectively, but none had t (9;22). Of those with high LAIR-1 expression, 2 had t (9;22) (MFIs-14.43 and 11.87). Conclusions: This pilot study of LAIR-1expression in ALL suggests low expression of the inhibitory molecule in leukemic cells. However, the findings need to be confirmed with larger cohort, along with studies focusing on pathophysiological roles in leukemic clone survival and escape from the immune system.

Bi W, Huang J, Nie C, et al.
CircRNA circRNA_102171 promotes papillary thyroid cancer progression through modulating CTNNBIP1-dependent activation of β-catenin pathway.
J Exp Clin Cancer Res. 2018; 37(1):275 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: As a type of recently discovered noncoding RNA, circular RNAs (circRNAs) exert pivot biological functions in diverse cancers. However, the role of circRNA_102171 in papillary thyroid cancer (PTC) has not been investigated. Our study was focused on the functional investigation toward circRNA_102171 in PTC progression. And we also aimed to reveal its potential molecular mechanism.
METHODS: The expression pattern of circRNA_102171 was determined using quantitative polymerase chain reaction (qPCR) in PTC samples and cell lines. Cell proliferation was examined utilizing CCK8, colony formation and EdU incorporation assays. Apoptosis was analyzed by Annexin V/PI staining and FACS detection. Cell migration and invasion was measured using Transwell assay. Tumor growth in vivo was determined through a xenograft assay. RNA-pulldown, RNA-IP (RIP) and RNA-EMSA were used to analyze the interaction between circRNA_102171 and CTNNBIP1.
RESULTS: CircRNA_102171 expression was upregulated in tumor tissues and cell lines. CircRNA_102171 silencing suppressed PTC cell proliferation, migration and invasion while promoting apoptosis. CircRNA_102171 knockdown inhibited PTC growth in vivo. CircRNA_102171 interacted with CTNNBIP1 to block its interaction with the β-catenin/TCF3/TCF4/LEF1 complex, leading to activation of Wnt/β-catenin pathway.
CONCLUSIONS: CircRNA_102171 overexpression promotes PTC progression through activating Wnt/β-catenin pathway in a CTNNBIP1-dependent way.

Yu D, Ye L
A Portrait of CXCR5
Trends Immunol. 2018; 39(12):965-979 [PubMed] Related Publications

Qin H, Ishii K, Nguyen S, et al.
Murine pre-B-cell ALL induces T-cell dysfunction not fully reversed by introduction of a chimeric antigen receptor.
Blood. 2018; 132(18):1899-1910 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Adoptive transfer of patient-derived T cells modified to express chimeric antigen receptors (CARTs) has demonstrated dramatic success in relapsed/refractory pre-B-cell acute lymphoblastic leukemia (ALL), but response and durability of remission requires exponential CART expansion and persistence. Tumors are known to affect T-cell function, but this has not been well studied in ALL and in the context of chimeric antigen receptor (CAR) expression. Using TCF3/PBX1 and MLL-AF4-driven murine ALL models, we assessed the impact of progressive ALL on T-cell function in vivo. Vaccines protect against TCF3/PBX1.3 but were ineffective when administered after leukemia injection, suggesting immunosuppression induced early during ALL progression. T cells from leukemia-bearing mice exhibited increased expression of inhibitory receptors, including PD1, Tim3, and LAG3, and were dysfunctional following adoptive transfer in a model of T-cell receptor (TCR)-dependent leukemia clearance. Although expression of inhibitory receptors has been linked to TCR signaling, pre-B-cell ALL induced inhibitory receptor expression, at least in part, in a TCR-independent manner. Finally, introduction of a CAR into T cells generated from leukemia-bearing mice failed to fully reverse poor in vivo function.

Kehl T, Schneider L, Kattler K, et al.
The role of TCF3 as potential master regulator in blastemal Wilms tumors.
Int J Cancer. 2019; 144(6):1432-1443 [PubMed] Related Publications
Wilms tumors are the most common type of pediatric kidney tumors. While the overall prognosis for patients is favorable, especially tumors that exhibit a blastemal subtype after preoperative chemotherapy have a poor prognosis. For an improved risk assessment and therapy stratification, it is essential to identify the driving factors that are distinctive for this aggressive subtype. In our study, we compared gene expression profiles of 33 tumor biopsies (17 blastemal and 16 other tumors) after neoadjuvant chemotherapy. The analysis of this dataset using the Regulator Gene Association Enrichment algorithm successfully identified several biomarkers and associated molecular mechanisms that distinguish between blastemal and nonblastemal Wilms tumors. Specifically, regulators involved in embryonic development and epigenetic processes like chromatin remodeling and histone modification play an essential role in blastemal tumors. In this context, we especially identified TCF3 as the central regulatory element. Furthermore, the comparison of ChIP-Seq data of Wilms tumor cell cultures from a blastemal mouse xenograft and a stromal tumor provided further evidence that the chromatin states of blastemal cells share characteristics with embryonic stem cells that are not present in the stromal tumor cell line. These stem-cell like characteristics could potentially add to the increased malignancy and chemoresistance of the blastemal subtype. Along with TCF3, we detected several additional biomarkers that are distinctive for blastemal Wilms tumors after neoadjuvant chemotherapy and that may provide leads for new therapeutic regimens.

Chen X, Wang F, Zhang Y, et al.
Retrospective analysis of 36 fusion genes in 2479 Chinese patients of de novo acute lymphoblastic leukemia.
Leuk Res. 2018; 72:99-104 [PubMed] Related Publications
Fusion genes are major molecular biological abnormalities in hematological malignancies. To depict the common recurrent gene-fusion landscape in acute lymphoblastic leukemia (ALL), 36 recurrent fusion genes in hematologic malignancies were assessed using multiplex-nested RT-PCR in 2479 patients with de novo ALL. 17 kinds of distinct fusion genes were detected in 712 (28.72%) cases. Co-occurrence of different fusion genes was observed in 6 (0.24%) patients. Incidence of fusion genes in B-ALL was significantly higher than in T-ALL (31.40% vs. 14.50%, P < 0.001). Pediatric ALL had higher prevalence of ETV6-RUNX1, TCF3-PBX1, and STIL-TAL1, while BCR-ABL1 and SET-NUP214 were more common in adult ALL. BCR-ABL1, TCF3-PBX1, KMT2A-AFF1 and ETV6-RUNX1 were more frequent in B-ALL. On the contrary, KMT2A-MLLT4, SET-NUP214 and STIL-TAL1 were of higher incidence in T-ALL. In comparison with Western cohorts, the incidence of BCR-ABL1 (5.94%) was much higher in our series, while the occurrence of ETV6-RUNX1 (13.19%) was significantly lower in pediatric B-ALL patients in our study than in Western reports. This study provides a genetic landscape of common fusion genes in ALL patients and may serve as a foundation for further improvement of a fusion gene screening panel for clinical applications.

Zhou X, Xian W, Zhang J, et al.
YY1 binds to the E3' enhancer and inhibits the expression of the immunoglobulin κ gene via epigenetic modifications.
Immunology. 2018; 155(4):491-498 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
The rearrangement and expression of immunoglobulin genes are regulated by enhancers and their binding transcriptional factors that activate or suppress the activities of the enhancers. The immunoglobulin κ (Igκ) gene locus has three important enhancers: the intrinsic enhancer (Ei), 3' enhancer (E3'), and distal enhancer (Ed). Ei and E3' are both required for Igκ gene rearrangement during early stages of B-cell development, whereas optimal expression of the rearranged Igκ gene relies on both E3' and Ed. The transcription factor YY1 affects the expression of many genes involved in B-cell development, probably by mediating interactions between their enhancers and promoters. Herein, we found that YY1 binds to the E3' enhancer and suppresses Igκ expression in B lymphoma cells by epigenetically modifying the enhancer. Knocking down YY1 enhanced Igκ expression, which was associated with increased levels of E2A (encoded by the TCF3 gene) and its binding to the E3' enhancer. Moreover, in germinal centre B cells and plasma cells, YY1 expression was reversely associated with Igκ levels, implying that YY1 might facilitate antibody affinity maturation in germinal centre B cells through the transient attenuation of Igκ expression.

Chen YS, Chang CW, Tsay YG, et al.
HSP40 co-chaperone protein Tid1 suppresses metastasis of head and neck cancer by inhibiting Galectin-7-TCF3-MMP9 axis signaling.
Theranostics. 2018; 8(14):3841-3855 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Human tumorous imaginal disc (Tid1), a DnaJ co-chaperone protein, is classified as a tumor suppressor. Previously, we demonstrated that Tid1 reduces head and neck squamous cell carcinoma (HNSCC) malignancy. However, the molecular details of Tid1-mediated anti-metastasis remain elusive.

Lin A, Cheng FWT, Chiang AKS, et al.
Excellent outcome of acute lymphoblastic leukaemia with TCF3-PBX1 rearrangement in Hong Kong.
Pediatr Blood Cancer. 2018; 65(12):e27346 [PubMed] Related Publications
OBJECTIVE: The aim of this study was to review clinical outcomes and prognosis of paediatric patients with acute lymphoblastic leukaemia (ALL) with TCF3-PBX1 rearrangement.
PATIENTS: All children in Hong Kong diagnosed with ALL with TCF3-PBX1 rearrangement over the past two decades were included.
METHODS: Six hundred and twenty-four newly diagnosed patients with ALL from four consecutive studies were enrolled from 1997 to 2016. Patients carrying TCF3-PBX1 rearrangement and patients at intermediate risk without the gene expression were compared for clinical characteristics, overall survival and event-free survival (EFS).
RESULTS: The TCF3-PBX1 rearrangement was detected in 30 of 624 patients (4.8%). Results were consistent across the consecutive clinical trials employed in the past two decades. Compared with 239 intermediate risk patients without TCF3-PBX1 rearrangement, the 5-year overall survival and EFS for patients with TCF3-PBX1 rearrangement was superior, with both at 100% (P = 0.12 and P = 0.029).
CONCLUSION: This population-based study over the past 20 years demonstrated that patients with TCF3-PBX1 rearrangement had favourable EFS compared with other intermediate risk patients treated with a similar chemotherapy backbone.

Oberley MJ, Gaynon PS, Bhojwani D, et al.
Myeloid lineage switch following chimeric antigen receptor T-cell therapy in a patient with TCF3-ZNF384 fusion-positive B-lymphoblastic leukemia.
Pediatr Blood Cancer. 2018; 65(9):e27265 [PubMed] Related Publications
A pediatric patient diagnosed initially with B-lymphoblastic leukemia (B-ALL) relapsed with lineage switch to acute myeloid leukemia (AML) after chimeric antigen receptor T-cell (CAR-T) therapy and hematopoietic stem cell transplant. A TCF3-ZNF384 fusion was identified at diagnosis, persisted through B-ALL relapse, and was also present in the AML relapse cell population. ZNF384-rearrangements define a molecular subtype of B-ALL characterized by a pro-B-cell immunophenotype; furthermore, ZNF384-rearrangements are prevalent in mixed-phenotype acute leukemias. Lineage switch following CAR-T therapy has been described in patients with KMT2A (mixed lineage leukemia) rearrangements, but not previously in any patient with ZNF384 fusion.

Hong Y, Zhao X, Qin Y, et al.
The prognostic role of E2A-PBX1 expression detected by real-time quantitative reverse transcriptase polymerase chain reaction (RQ-PCR) in B cell acute lymphoblastic leukemia after allogeneic hematopoietic stem cell transplantation.
Ann Hematol. 2018; 97(9):1547-1554 [PubMed] Related Publications
The E2A-PBX1 rearrangement is common in B cell acute lymphoblastic leukemia (B-ALL). However, whether this fusion gene can be used as a reliable marker for minimal residual disease (MRD) following allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains unknown. In this study, clinical data were collected from 28 consecutive B-ALL patients who received allo-HSCT. Their MRD was evaluated by E2A-PBX1 and leukemia-associated immunophenotype (LAIP). The median follow-up was 374 days (55-2342 days). Of the enrolled patients, seven (25%) patients died of leukemia relapse. A total of nine (32.1%) patients experienced relapse at a median of 164 days (75-559 days) after transplantation. The median expression level in the first positive sample was 0.14% (0.0071-902.4%). The duration from E2A-PBX1-positive results to hematological relapse was 74 days (30-469 days). E2A-PBX1 expression generally became positive prior to flow cytometry. Patients with positive E2A-PBX1 gene expression pre-transplantation were more likely to have positive E2A-PBX1 expression after transplantation. Taken all together, E2A-PBX1 expression determined by real-time quantitative reverse transcriptase polymerase chain reaction (RQ-PCR) could be used to evaluate MRD status after allo-HSCT. Patients with positive E2A-PBX1 expression after transplant will have a poor prognosis.

Takahashi H, Kajiwara R, Kato M, et al.
Treatment outcome of children with acute lymphoblastic leukemia: the Tokyo Children's Cancer Study Group (TCCSG) Study L04-16.
Int J Hematol. 2018; 108(1):98-108 [PubMed] Related Publications
The survival rate of children with acute lymphoblastic leukemia (ALL) has increased to approximately 90% after substantial progress in risk-oriented treatment strategies. Between 2005 and 2013, the Tokyo Children's Cancer Study Group (TCCSG) conducted a risk-oriented, non-randomized study, L04-16. The principal aim of this study was to assemble background characteristics and treatment outcomes, and gather genetic information on leukemic cells under central diagnosis. This report outlines the background characteristics and treatment outcomes of 1033 children with ALL treated according to a TCCSG platform. The 5-year event-free and overall survival (OS) rates for all children were 78.1 ± 1.3 and 89.6 ± 1.0%, respectively. The OS rate was significantly higher in children with B-cell precursor (BCP)-ALL (91.9 ± 1.0%, n = 916) than in those with T-ALL (71.9 ± 4.3%, n = 117, p < 0.001). In univariate analysis for BCP-ALL, children aged 1-6 years (5y-OS: 94.2 ± 1.0%), with an initial white blood cell count of < 20,000/μL (94.0 ± 1.0%), high hyperdiploidy (95.4 ± 1.6%), ETV6-RUNX1 (97.4 ± 1.2%) or TCF3-PBX1 (96.9 ± 2.1%), and "Day8NoBlasts" (96.4 ± 1.1%) had the best outcomes. Genetic investigation revealed two novel fusion genes within this cohort: ETV6-ZNF385A and ZNF362-TCF4. Our study highlighted the clinical aspects of genomic features of ALL in Japanese children. We provide fundamental information for the further molecular investigation of this disease.

Singh M, Bhatia P, Trehan A, et al.
High frequency of intermediate and poor risk copy number abnormalities in pediatric cohort of B-ALL correlate with high MRD post induction.
Leuk Res. 2018; 66:79-84 [PubMed] Related Publications
Copy number abnormalities (CNAs) and recurrent fusion transcripts are important genetic events which define and prognosticate B-Cell Acute Lymphoblastic Leukemia (B-ALL). We evaluated CNAs and fusion transcripts in 67 pediatric B-ALL cases and correlated the data with standard risk factors and early treatment outcome parameters. Common fusion transcripts ETV6-RUNX1, E2A-PBX, BCR-ABL1 and MLL-AF4 were examined by RT-PCR and noted in 15%, 15%, 13% and 1.4% of all cases respectively. CNAs in IKZF1, PAX5, EBF1, BTG1, RB1, CDKN2A/B and genes from PAR1 region viz., CSF2RA, IL3RA,P2RY8, SHOX region and CRLF2 were analyzed by multiplex ligation dependent probe amplification assay and were detected in 70% (47/67) of cases, with predominantly deletions in CDKN2A/B (36%), PAX5 (18%) and IKZF1 (16%). A statistically significant association of intermediate/poor risk CNAs was noted with high WBC count (p = 0.001), NCI group (p = 0.02) and minimal residual disease at Day35 (p < 0.0001). IKZF1 and CDKN2A/B deletion revealed poor EFS of 56% at 24 months as compared to EFS of 80% in rest of the cases (p = 0.05) suggesting their potential role in early risk stratification.

Kachroo P, Szymczak S, Heinsen FA, et al.
NGS-based methylation profiling differentiates TCF3-HLF and TCF3-PBX1 positive B-cell acute lymphoblastic leukemia.
Epigenomics. 2018; 10(2):133-147 [PubMed] Related Publications
AIM: To determine whether methylation differences between mostly fatal TCF3-HLF and curable TCF3-PBX1 pediatric acute lymphoblastic leukemia subtypes can be associated with differential gene expression and remission.
MATERIALS & METHODS: Five (extremely rare) TCF3-HLF versus five (very similar) TCF3-PBX1 patients were sampled before and after remission and analyzed using reduced representation bisulfite sequencing and RNA-sequencing.
RESULTS: We identified 7000 differentially methylated CpG sites between subtypes, of which 78% had lower methylation levels in TCF3-HLF. Gene expression was negatively correlated with CpG sites in 23 genes. KBTBD11 clearly differed in methylation and expression between subtypes and before and after remission in TCF3-HLF samples.
CONCLUSION: KBTBD11 hypomethylation may be a promising potential target for further experimental validation especially for the TCF3-HLF subtype.

Gordiienko I, Shlapatska L, Kholodniuk VM, et al.
CD150 and CD180 are involved in regulation of transcription factors expression in chronic lymphocytic leukemia cells.
Exp Oncol. 2017; 39(4):291-298 [PubMed] Related Publications
BACKGROUND: Sequential stages of B-cell development is stringently coordinated by transcription factors (TFs) network that include B-lineage commitment TFs (Ikaros, Runx1/Cbfb, E2A, and FOXO1), B-lineage maintenance TFs (EBF1 and PAX5) and stage specific set of TFs (IRF4, IRF8, BCL6, BLIMP1). Deregulation of TFs expression and activity is often occurs in malignant B cells. The aim of this study was to evaluate TFs expression in chronic lymphocytic leukemia cells taking into consideration CD150 cell surface expression. From other side we attempted to regulate TFs expression via CD150 and CD180 cell surface receptors.
MATERIALS AND METHODS: Studies were performed on normal peripheral blood B-cell subpopulations and chronic lymphocytic leukemia (CLL) cells isolated from peripheral blood of 67 primary untreated patients with CLL. Evaluation of TFs expression was performed on mRNA level using qRT-PCR and on protein level by western blot analysis.
RESULTS: Median of PAX5 and EBF1 mRNA expression was higher in cell surface CD150 positive (csCD150
CONCLUSIONS: Analysis of TFs expression profile revealed upregulated SPIB mRNA level and downregulated PU.1 in CLL cells. CD150 and CD180 receptors may modulate transcriptional program in CLL cells by regulating the TFs expression levels.

Zhan D, Zhang Y, Xiao P, et al.
Whole exome sequencing identifies novel mutations of epigenetic regulators in chemorefractory pediatric acute myeloid leukemia.
Leuk Res. 2018; 65:20-24 [PubMed] Related Publications
Genomic alterations underlying chemotherapy resistance remains poorly characterized in pediatric acute myeloid leukemia (AML). In this study, we used whole exome sequencing to identify gene mutations associated with chemo-resistance in 44 pediatric AML patients. We identified previously unreported mutations involving epigenetic regulators such as KDM5C, SRIT6, CHD4, and PRPF6 in pediatric AML patients. Despite low prevalence in general pediatric AML, mutations involving epigenetic regulators including splicing factors, were collectively enriched as a group in primary chemo-resistance AML patients. In addition, clonal evolution analysis of secondary chemo-resistance AML patients reveals dominant clone at diagnosis could survive several course of intensified chemotherapy. And gain of new mutations in genes such as MVP, TCF3, SS18, and BCL10, may contribute to chemo-resistance at relapse. These results provide novel insights into the genetic basis of treatment failure in pediatric AML.

Mayoral-Varo V, Calcabrini A, Sánchez-Bailón MP, Martín-Pérez J
miR205 inhibits stem cell renewal in SUM159PT breast cancer cells.
PLoS One. 2017; 12(11):e0188637 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
miR205 has a dual activity, as tumor suppressor and as oncogene. Here we analyzed the impact of miR205 ectopic expression in the initial tumorigenic processes of SUM159PT, a triple negative breast cancer cell line with low endogenous levels of miR205. In SUM159PT, miR205 inhibited expression of its targets VEGFA, ErbB3, Zeb1, Fyn and Lyn A/B; it reduced cell proliferation, and Myc/cyclin D1 levels, while increased p27kip1 expression. miR205 abolished anchorage-independent growth, inhibited migration and invasion, Src-kinases/Stat3 axis activation, and levels of secreted MMP9. miR205 also reduced expression of CD44 and TAZ, E2A.E12, Twist, Snail1 and CK5, associated with epithelial-mesenchymal transition (EMT). Importantly, we show that miR205 inhibited SUM159PT cancer-stem cell renewal, expression in mammospheres of CD44 and ALDH1 stem-cell markers, TAZ, and E2A.E12. All these effects of miR205 were reverted by Anti-miR205 co-expression, demonstrating its specificity. Thus, all these results strongly suggest that ectopic expression of miR205 in SUM159PT affected several parameters associated with initial steps of tumorigenesis.

Jerchel IS, Hoogkamer AQ, Ariës IM, et al.
RAS pathway mutations as a predictive biomarker for treatment adaptation in pediatric B-cell precursor acute lymphoblastic leukemia.
Leukemia. 2018; 32(4):931-940 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
RAS pathway mutations have been linked to relapse and chemotherapy resistance in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL). However, comprehensive data on the frequency and prognostic value of subclonal mutations in well-defined subgroups using highly sensitive and quantitative methods are lacking. Targeted deep sequencing of 13 RAS pathway genes was performed in 461 pediatric BCP-ALL cases at initial diagnosis and in 19 diagnosis-relapse pairs. Mutations were present in 44.2% of patients, with 24.1% carrying a clonal mutation. Mutation frequencies were highest in high hyperdiploid, infant t(4;11)-rearranged, BCR-ABL1-like and B-other cases (50-70%), whereas mutations were less frequent in ETV6-RUNX1-rearranged, and rare in TCF3-PBX1- and BCR-ABL1-rearranged cases (27-4%). RAS pathway-mutated cells were more resistant to prednisolone and vincristine ex vivo. Clonal, but not subclonal, mutations were linked to unfavorable outcome in standard- and high-risk-treated patients. At relapse, most RAS pathway mutations were clonal (9 of 10). RAS mutant cells were sensitive to the MEK inhibitor trametinib ex vivo, and trametinib sensitized resistant cells to prednisolone. We conclude that RAS pathway mutations are frequent, and that clonal, but not subclonal, mutations are associated with unfavorable risk parameters in newly diagnosed pediatric BCP-ALL. These mutations may designate patients eligible for MEK inhibitor treatment.

Liang DC, Chen SH, Liu HC, et al.
Mutational status of NRAS, KRAS, and PTPN11 genes is associated with genetic/cytogenetic features in children with B-precursor acute lymphoblastic leukemia.
Pediatr Blood Cancer. 2018; 65(2) [PubMed] Related Publications
BACKGROUND: We aimed to investigate the frequencies and the association with genetic/cytogenetic abnormalities as well as prognostic relevance of RAS pathway mutations in Taiwanese children with B-precursor acute lymphoblastic leukemia (ALL), the largest cohort in Asians.
PROCEDURE: Between 1995 and 2012, marrow samples at diagnosis from 535 children were studied for NRAS, KRAS, and PTPN11 mutations. The mutational status of each gene was correlated with the clinico-hematological features, recurrent genetic abnormalities, and outcomes for those treated with TPOG-ALL-2002 protocol (n = 346).
RESULTS: The frequencies of NRAS, KRAS, and PTPN11 mutations were 10.8% (57/530), 10.2% (54/530), and 3.0% (16/526), respectively. NRAS mutations were associated with a higher frequency of hyperdiploidy (P = 0.01) and lower frequency of ETV6-RUNX1 (P < 0.01), whereas KRAS mutations were associated with younger age (P < 0.01), a higher frequency of KMT2A rearranged (P < 0.01) but no significant difference if infants with ALL were excluded, and inferior event-free survival (66.6% vs. 80.5%, P = 0.04). None of patients with TCF3-PBX1 had KRAS mutation (P = 0.02).
CONCLUSIONS: Our study showed that the frequency of KRAS mutations in Taiwan was significantly higher than that reported in Caucasians. The occurrence of RAS pathway mutations was associated with recurrent genetic/cytogenetic abnormalities in pediatric B-precursor ALL.

Yochum ZA, Cades J, Mazzacurati L, et al.
A First-in-Class TWIST1 Inhibitor with Activity in Oncogene-Driven Lung Cancer.
Mol Cancer Res. 2017; 15(12):1764-1776 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
TWIST1, an epithelial-mesenchymal transition (EMT) transcription factor, is critical for oncogene-driven non-small cell lung cancer (NSCLC) tumorigenesis. Given the potential of TWIST1 as a therapeutic target, a chemical-bioinformatic approach using connectivity mapping (CMAP) analysis was used to identify TWIST1 inhibitors. Characterization of the top ranked candidates from the unbiased screen revealed that harmine, a harmala alkaloid, inhibited multiple TWIST1 functions, including single-cell dissemination, suppression of normal branching in 3D epithelial culture, and proliferation of oncogene driver-defined NSCLC cells. Harmine treatment phenocopied genetic loss of

Malouf C, Ottersbach K
Molecular processes involved in B cell acute lymphoblastic leukaemia.
Cell Mol Life Sci. 2018; 75(3):417-446 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
B cell leukaemia is one of the most frequent malignancies in the paediatric population, but also affects a significant proportion of adults in developed countries. The majority of infant and paediatric cases initiate the process of leukaemogenesis during foetal development (in utero) through the formation of a chromosomal translocation or the acquisition/deletion of genetic material (hyperdiploidy or hypodiploidy, respectively). This first genetic insult is the major determinant for the prognosis and therapeutic outcome of patients. B cell leukaemia in adults displays similar molecular features as its paediatric counterpart. However, since this disease is highly represented in the infant and paediatric population, this review will focus on this demographic group and summarise the biological, clinical and epidemiological knowledge on B cell acute lymphoblastic leukaemia of four well characterised subtypes: t(4;11) MLL-AF4, t(12;21) ETV6-RUNX1, t(1;19) E2A-PBX1 and t(9;22) BCR-ABL1.

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