Affinage

TCL1A

T-cell leukemia/lymphoma protein 1A · UniProt P56279

Length
114 aa
Mass
13.5 kDa
Annotated
2026-06-10
100 papers in source corpus 30 papers cited in narrative 30 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TCL1A encodes a small 14 kDa beta-barrel protein that acts as a co-activator of AKT kinase, coupling antigen-receptor signaling to cell survival, proliferation, and clonal expansion in lymphoid cells (PMID:10716693, PMID:10983986). It binds the AKT pleckstrin homology domain at a hydrophobic surface (residues D16 and I74) opposite the phospholipid-binding pocket, while a separate beta-C-sheet homodimerization interface allows dimeric TCL1 to crosslink and oligomerize AKT molecules at the membrane, driving trans-phosphorylation, nuclear translocation, and a 5–10-fold enhancement of kinase activity; both the AKT-binding and oligomerization domains are required for full activity (PMID:11839817, PMID:15169787). TCL1 is recruited together with AKT to transient TCR- and BCR-associated membrane activation complexes containing receptor-proximal kinases, where its abundance tunes the strength and kinetics of AKT phospho-activation and the proliferative response (PMID:17890451, PMID:19770358). Beyond AKT, TCL1 rewires transcription and chromatin: it represses AP-1 by binding c-Jun/JunB/c-Fos, activates NF-κB through p300/CBP and through an ATM complex that drives IκBα phosphorylation, and inhibits the de novo methyltransferase DNMT3A to reduce global DNA methylation (PMID:19064921, PMID:22065599, PMID:22308499). It also reprograms metabolism, acting through hnRNPK-dependent G6PD splicing and through PNPase to shift cells toward glycolysis (PMID:24352616, PMID:28262547). TCL1 is essential for normal B- and T-lymphocyte development and suppresses activation-induced cell death (PMID:15479728, PMID:17846228). Its expression is tightly controlled by Sp1-driven promoter activity, promoter CpG (de)methylation, the TORC2 axis, and multiple microRNAs (miR-29, miR-181, miR-3676) (PMID:12421830, PMID:11241786, PMID:17548807, PMID:17178851, PMID:25646413). TCL1A expression also drives expansion of TET2- and ASXL1-mutated hematopoietic stem cell clones in clonal hematopoiesis, and an inherited protective promoter polymorphism restricting its expression dampens this expansion (PMID:37046083).

Mechanistic history

Synthesis pass · year-by-year structured walk · 22 steps
  1. 1994 Medium

    Before functional characterization, the basic biochemical identity of the TCL1 product needed definition; this established it as a small intracellular protein associated with the microsomal fraction.

    Evidence Bacterial expression, antisera, cell fractionation and confocal microscopy

    PMID:7987816

    Open questions at the time
    • No molecular activity assigned at this stage
    • Microsomal association not reconciled with later membrane/nuclear localization
  2. 2000 High

    The central question of what TCL1 does molecularly was answered by showing it binds the AKT PH domain and enhances AKT kinase activity, establishing TCL1 as an AKT co-activator that promotes survival and proliferation.

    Evidence Endogenous co-IP, domain-mapping deletion constructs, in vitro kinase assays, immunofluorescence, yeast two-hybrid, and mitochondrial potential assays in two independent studies

    PMID:10716693 PMID:10983986

    Open questions at the time
    • Structural basis of the interface not yet resolved
    • Mechanism of AKT oligomerization inferred indirectly
  3. 2001 High

    Whether TCL1 acts on all AKT isoforms was addressed by demonstrating PH-domain-determined specificity and TCL1-facilitated hetero-oligomerization and transphosphorylation among AKT isoforms.

    Evidence Endogenous co-IP in leukemia/lymphoma lines, in vitro kinase assays, and chimeric AKT1/AKT3 PH-domain constructs

    PMID:11707444

    Open questions at the time
    • Single-lab isoform specificity data
    • Functional consequences of isoform-specific binding not dissected
  4. 2002 High

    The structural determinants of TCL1 function were mapped, showing distinct AKT-association (D16/I74) and homodimerization (beta-C sheet) domains are both required for AKT activation and downstream cellular effects.

    Evidence Random mutagenesis loss-of-interaction yeast two-hybrid screen, molecular modeling, in vitro kinase assays, and cellular functional readouts; complementary site-directed mutagenesis with in vitro complex formation

    PMID:11839817 PMID:12009899

    Open questions at the time
    • Structure inferred from modeling rather than a solved complex
    • Optimal membrane-extract complex formation not mechanistically explained
  5. 2002 High

    How TCL1 transcription is controlled was first defined by identifying Sp1 as the transactivator of its core promoter and mapping the transcriptional start sites.

    Evidence 5' RACE, luciferase reporters, Sp1 dose-dependent transactivation in Sp1-null SL2 cells, mutagenesis, and EMSA

    PMID:12421830

    Open questions at the time
    • Tissue-specific regulation not addressed
    • Interplay with later-identified methylation/miRNA controls not integrated
  6. 2002 Medium

    A physiological developmental role independent of cancer was established by showing maternal TCL1 shuttles in early embryos and is needed for cleavage and morula development.

    Evidence Tcl1-deficient mice and immunofluorescence of early embryos with in vitro development scoring

    PMID:12181493

    Open questions at the time
    • Molecular partners in embryos not identified
    • Connection to AKT activity in this context untested
  7. 2004 High

    The biophysical mechanism of activation was resolved by structural methods showing dimeric TCL1 crosslinks two AKT molecules in a preactivated conformation at a site opposite the lipid pocket.

    Evidence Fluorescence anisotropy, NMR, and SAXS to define affinities, interfaces, and a low-resolution complex; complemented by an Akt-in inhibitory peptide tested in vitro and in vivo

    PMID:15169787 PMID:15459205

    Open questions at the time
    • Only low-resolution complex structure available
    • How crosslinking hinders deactivation not directly demonstrated
  8. 2004 High

    The organismal requirement for TCL1 in immunity was defined, showing it is needed for normal B- and T-cell development and antibody responses.

    Evidence Tcl1-knockout mice with flow cytometry, apoptosis assays, and T-dependent immunization

    PMID:15479728

    Open questions at the time
    • Molecular pathway linking TCL1 loss to developmental blocks not fully traced
    • Cell-intrinsic vs extrinsic effects not separated
  9. 2006 Medium

    Mechanisms restraining TCL1 expression were uncovered, linking promoter hypomethylation to oncogenic activation and miR-29/miR-181 to its repression in CLL.

    Evidence NotI methylation analysis with 5-azacytidine demethylation; miRNA expression profiling correlated with TCL1 protein in CLL samples

    PMID:11241786 PMID:17178851

    Open questions at the time
    • Direct 3'UTR targeting by miR-29/miR-181 not shown in these reports
    • Causal vs correlative relationship for miRNAs incomplete
  10. 2006 Medium

    TCL1 partner space was extended to PNPase, showing a binding event through its AKT-interaction domain that does not alter PNPase RNA-degrading activity.

    Evidence Co-IP, in vitro RNA degradation assay, and computational docking

    PMID:16934922

    Open questions at the time
    • Functional consequence of the interaction unclear at this stage
    • Single-lab co-IP
  11. 2006 Medium

    The receptor-proximal context of TCL1–AKT signaling was defined by showing co-recruitment to transient TCR membrane complexes with LCK and that TCL1 levels tune AKT activation kinetics.

    Evidence Co-IP from primary T-PLL tumors and TCL1-transfected lines, subcellular fractionation, AKT inhibition, and TCL1 overexpression/knockdown

    PMID:17890451

    Open questions at the time
    • Composition of activation complexes incompletely defined
    • Single-lab data
  12. 2007 Medium

    An anti-apoptotic mechanism in T cells was identified, showing TCL1 blocks PKCθ and ERK activation to suppress activation-induced cell death.

    Evidence Gain- and loss-of-function in Jurkat and SUP-T11 cells, AICD assays, phospho-readouts, and primary T-PLL analysis

    PMID:17846228

    Open questions at the time
    • Whether PKCθ/ERK suppression is AKT-dependent not resolved
    • Single-lab
  13. 2007 Medium

    A signaling-responsive transcriptional control circuit was defined, showing TORC2 directly regulates TCL1 and GC signaling via CD40/BCR represses it independently of CREB Ser-133.

    Evidence Promoter reporters, TORC2 phosphorylation/localization studies, pharmacological CD40/BCR and cAMP manipulation, and ChIP

    PMID:17548807

    Open questions at the time
    • Direct TORC2 occupancy specificity not fully mapped
    • Single-lab
  14. 2008 High

    TCL1 was shown to act as a transcriptional modulator beyond AKT, repressing AP-1 via Jun/Fos binding and activating NF-κB via p300/CBP, with CLL mutations enhancing AP-1 inhibition.

    Evidence Reciprocal co-IP, AP-1/NF-κB reporter assays, sequencing of 600 B-CLL samples, and gain-of-function mutagenesis

    PMID:19064921

    Open questions at the time
    • Direct DNA-binding vs cofactor sequestration mechanism not distinguished
    • Single-lab
  15. 2009 Medium

    A viral route to TCL1 repression was established, showing EBV LMP1 down-regulates TCL1 by inducing miR-29b through p38 MAPK.

    Evidence miRNA profiling of LMP1 transfectants, LNA antisense rescue, and p38/MAPK inhibition

    PMID:19966860

    Open questions at the time
    • Direct miR-29b–TCL1 3'UTR engagement inferred
    • Single-lab
  16. 2011 High

    TCL1's NF-κB activation and AP-1-linked tumor-suppressor silencing were mechanistically extended, identifying an ATM complex driving IκBα turnover and AP-1-mediated repression of PTPROt.

    Evidence Mass spectrometry and co-IP for TCL1–ATM with IκBα phosphorylation/ubiquitination assays; PTPROt promoter reporters, ChIP for c-Fos/c-Jun, and transgenic mouse B cells

    PMID:22001392 PMID:22065599

    Open questions at the time
    • Whether ATM kinase activity is required not resolved
    • Single-lab for each axis
  17. 2012 High

    TCL1 was linked to epigenetic and ER-stress reprogramming, inhibiting DNMT3A to lower global methylation and associating with XBP-1 to activate the IRE-1/XBP-1 pathway.

    Evidence MS/proteomics, co-IP, in vitro DNMT3A activity assay, genome-wide methylation in transgenic mice; co-IP and pathway inhibitor experiments in vitro and in vivo for XBP-1

    PMID:22308499 PMID:22692508

    Open questions at the time
    • Direct vs indirect DNMT3A inhibition mechanism unresolved
    • Downstream methylation targets not specified
  18. 2013 High

    Metabolic and receptor co-receptor roles were defined, showing TCL1 promotes hnRNPK-dependent G6PD splicing/PPP flux and forms a complex with ROR1 that amplifies AKT activation.

    Evidence Co-IP, G6PD splicing and PPP flux assays, GSK3β/PTEN epistasis, mouse tumor models; MS-validated ROR1 co-IP with transgenic crosses and anti-ROR1 mAb treatment

    PMID:24352616 PMID:24379361

    Open questions at the time
    • Direct ROR1–TCL1 binding interface unmapped
    • Tissue specificity of G6PD effect unclear
  19. 2015 Medium

    BCR-coupled signaling and microRNA control were refined, showing TCL1–AKT co-recruitment to BCR complexes predicts proliferative response and miR-3676 directly represses TCL1 via its 3'UTR.

    Evidence Co-IP of BCR activation complexes from primary CLL with phospho-AKT correlation across 70 cases; 3'UTR reporter assays and sequencing of 539 CLL samples

    PMID:19770358 PMID:25646413

    Open questions at the time
    • Causality of TCL1 level vs disease aggressiveness correlative
    • Single-lab
  20. 2017 Medium

    A developmental/metabolic switch role was established, showing KLF4-induced TCL1 drives a glycolytic shift during iPSC reprogramming via AKT activation and PNPase counteraction.

    Evidence KLF4-dependent reprogramming screen, metabolic flux measurements, TCL1 and AKT perturbation, and PNPase interaction assays

    PMID:28262547

    Open questions at the time
    • Mechanism of PNPase counteraction not biochemically defined
    • Single-lab
  21. 2020 Medium

    TCL1A's role in lowering activation thresholds was quantified in T-PLL, showing enhanced TCR kinase activation, NFAT/JAK-STAT responses, reduced IL-2 threshold, and death resistance.

    Evidence Forced TCL1A expression, phospho-flow, reporter assays, and in vivo leukemogenesis models

    PMID:33301031

    Open questions at the time
    • Direct molecular targets in TCR proximal signaling not pinpointed
    • Single-lab
  22. 2023 High

    A causal role in clonal hematopoiesis was established, showing TET2/ASXL1 mutations induce TCL1A, that TCL1A drives HSC expansion, and that a protective promoter polymorphism restricts mutant clone expansion.

    Evidence GWAS of clonal expansion rates, forced expression and knockdown in human and mouse HSCs, and in vivo transplantation

    PMID:37046083

    Open questions at the time
    • Why DNMT3A-mutated clones are independent of TCL1A unresolved
    • Downstream effector of HSC expansion not fully defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how TCL1's many partner interactions (AKT, ATM, DNMT3A, AP-1, XBP-1, PNPase, hnRNPK, ROR1) are coordinated within a cell and which are direct effectors versus context-specific, and a high-resolution structure of the TCL1–AKT complex is still lacking.
  • No solved high-resolution TCL1–AKT complex structure
  • Hierarchy and mutual exclusivity of TCL1 partner interactions undefined
  • Mechanism by which a single small protein integrates kinase, transcriptional, epigenetic, and metabolic outputs unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0140096 catalytic activity, acting on a protein 3 GO:0060090 molecular adaptor activity 2 GO:0140110 transcription regulator activity 2
Localization
GO:0005634 nucleus 3 GO:0005886 plasma membrane 3 GO:0005829 cytosol 2
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-1430728 Metabolism 2 R-HSA-4839726 Chromatin organization 1 R-HSA-5357801 Programmed Cell Death 1
Partners
AKT1AKT3ATMC-JUNDNMT3AHNRNPKROR1XBP-1
Complex memberships
TCL1–AKT complexTCL1–ATM complexTCR/BCR membrane activation complex

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 TCL1 physically interacts with AKT1 through the pleckstrin homology (PH) domain of AKT1; endogenous AKT1 bound to TCL1 is 5–10 times more kinase-active than unbound AKT1; and TCL1 promotes nuclear translocation of AKT1 (AKT1 found only in cytoplasm alone, but also in nucleus when co-expressed with TCL1). Co-immunoprecipitation of endogenous proteins in SupT11 T-cell leukemia line; co-transfection in 293 cells with AKT1 deletion constructs; in vitro kinase assay; immunofluorescence localization in mouse fibroblasts Proceedings of the National Academy of Sciences of the United States of America High 10716693
2000 TCL1 binds the AKT PH domain and, both in vitro and in vivo, increases AKT kinase activity and substrate phosphorylation; TCL1 forms trimers that associate with AKT and facilitates AKT oligomerization and activation; TCL1 stabilizes mitochondrial transmembrane potential and enhances cell proliferation and survival. Yeast two-hybrid screening; in vitro kinase assay; in vivo overexpression assays; mitochondrial membrane potential assay Molecular cell High 10983986
2001 Unlike Akt1 and Akt2, Akt3 specifically interacts with TCL1 but not with MTCP1 or TCL1b; this specificity is determined by the Akt PH domain; TCL1 enhances hetero-oligomerization of Akt1 with Akt3 and facilitates Akt transphosphorylation; TCL1 interacts with endogenous Akt1, Akt2, and Akt3 in TCL1-overexpressing cell lines. Co-immunoprecipitation with endogenous proteins in leukemia/lymphoma cell lines; in vitro kinase assays; chimeric Akt1/Akt3 PH domain constructs; mammalian overexpression The Journal of biological chemistry High 11707444
2002 Residues D16 and I74 on TCL1 mediate association with AKT; the beta-C sheet of TCL1 mediates homodimerization; both the Akt-association domain and the oligomerization domain are required for TCL1-induced Akt activation and substrate phosphorylation; both domains are also required for full TCL1 function in vivo (mitochondrial permeability, nuclear translocation, cell survival). PCR-generated random TCL1 library + yeast two-hybrid loss-of-interaction screen; molecular modeling; in vitro kinase assays; mammalian overexpression; mitochondrial permeability assay; immunofluorescence Molecular and cellular biology High 11839817
2002 TCL1 possesses a modeled hydrophobic patch composed of two discontinuous amino acid stretches near one end of its beta-barrel; site-directed mutations of this region disrupt TCL1–AKT interaction without altering TCL1 secondary structure; TCL1 and AKT co-localize in multiple cell compartments but plasma membrane extracts optimally support complex formation in vitro. Molecular modeling; site-directed mutagenesis; in vitro complex formation assay with subcellular fractions; co-immunoprecipitation; immunofluorescence co-localization Biochemistry Medium 12009899
2004 TCL1 and its homologue MTCP1 bind the PKB/AKT pleckstrin homology domain at a site opposite the phospholipid binding pocket; dimeric TCL1 crosslinks two PKB molecules at the membrane in a preactivated conformation, potentially promoting trans-phosphorylation and hindering PKB deactivation. Fluorescence anisotropy; NMR spectroscopy; small-angle X-ray scattering (SAXS) to determine affinities, molecular interfaces, and low-resolution complex structure The Journal of biological chemistry High 15169787
2004 A peptide ('Akt-in') spanning the betaA strand of TCL1 interacts with the AKT PH domain, prevents phosphoinositide binding, inhibits AKT membrane translocation and kinase activation, and reduces cell proliferation, apoptosis resistance, and tumor growth in vivo. NMR conformational studies; in vitro kinase assays; phosphoinositide binding assays; cell proliferation and apoptosis assays; in vivo tumor growth assay The Journal of biological chemistry High 15459205
2006 miR-29 and miR-181 regulate TCL1 expression in CLL; their expression levels inversely correlate with TCL1 protein levels in CLL samples. microRNA expression profiling of CLL patient samples; correlation of miRNA vs. TCL1 protein levels (Western blot/flow cytometry) Cancer research Medium 17178851
2008 TCL1 physically interacts with c-Jun, JunB, and c-Fos and inhibits AP-1 transcriptional activity; TCL1 activates NF-κB by physically interacting with p300/CREB binding protein; TCL1 mutations T38I and R52H found in B-CLL samples are gain-of-function mutants as AP-1 inhibitors. Co-immunoprecipitation; transcriptional reporter assays (AP-1 and NF-κB luciferase); sequencing of 600 B-CLL samples; gain-of-function mutagenesis Proceedings of the National Academy of Sciences of the United States of America High 19064921
2011 TCL1 physically interacts with ATM (ataxia-telangiectasia mutated) protein; the TCL1–ATM complex leads to enhanced IκBα phosphorylation and ubiquitination, resulting in activation of the NF-κB pathway. Mass spectrometry to identify TCL1 interacting proteins; co-immunoprecipitation validation of TCL1–ATM complex; IκBα phosphorylation and ubiquitination assays Blood High 22065599
2012 TCL1 physically interacts with de novo DNA methyltransferases DNMT3A and DNMT3B; TCL1 overexpression drastically inhibits DNMT3A enzymatic activity; B cells from TCL1 transgenic mice show significantly decreased global DNA methylation compared to wild-type controls. Proteomics/mass spectrometry to identify TCL1 interacting partners; co-immunoprecipitation; DNMT3A in vitro enzymatic activity assay; genome-wide DNA methylation analysis Proceedings of the National Academy of Sciences of the United States of America High 22308499
2013 TCL1 promotes G6PD pre-mRNA splicing and G6PD protein expression in an hnRNPK-dependent manner; TCL1 acts as a co-activator for AKT to reverse PTEN-mediated inhibition of the pentose phosphate pathway; PTEN inactivates TCL1 via GSK3β-mediated phosphorylation of TCL1. Molecular biology and biochemistry assays; mass spectrometry; co-immunoprecipitation; G6PD splicing assays; PPP flux measurements; siRNA knockdown; mouse tumor formation assays Gut High 24352616
2006 TCL1 and AKT are recruited together to transient membrane activation complexes upon TCR engagement in T-PLL; these complexes include TCR-associated tyrosine kinases LCK; AKT inhibition alters localization, stability, and levels of TCL1–AKT complexes; introduction and knockdown of TCL1 influence kinetics and strength of TCR-mediated AKT activation. Co-immunoprecipitation from primary T-PLL tumors and TCL1-transfected T-cell lines; subcellular fractionation; pharmacological AKT inhibition; TCL1 overexpression and siRNA knockdown Blood Medium 17890451
2007 TCL1 inhibits activation-induced cell death (AICD) in T cells by blocking PKCθ and ERK pathway activation upon cellular stimulation; in TCL1-driven T-cell leukemia line SUP-T11, PKCθ and ERK phosphorylation are impaired and restored by TCL1 knockdown via RNA interference. TCL1 overexpression in Jurkat cells; AICD assay; phospho-flow/Western blot for PKCθ and ERK; RNA interference (TCL1 knockdown) in SUP-T11; analysis of primary T-PLL and normal T lymphocytes transduced with TCL1 Blood Medium 17846228
2007 TORC2 (CREB coactivator) directly regulates TCL1 expression; germinal center signaling through CD40 or BCR causes TORC2 phosphorylation, cytosolic emigration, and TCL1 repression independently of CREB Ser-133 phosphorylation and CBP/p300 recruitment; cAMP-inducible pathways inhibit this TCL1 repression. Reporter assays for TCL1 promoter activity; TORC2 phosphorylation and subcellular localization studies; pharmacological activation of CD40/BCR and cAMP pathways; ChIP Proceedings of the National Academy of Sciences of the United States of America Medium 17548807
2006 TCL1 oncogene is activated in Burkitt's lymphoma by promoter hypomethylation (loss of methylation at a NotI CpG site near the TATA box) rather than chromosomal rearrangement; experimental demethylation of methylated alleles induces TCL1 expression in vitro. Southern blot/restriction analysis for NotI site methylation; 5-azacytidine demethylation in cell lines; correlation of methylation status with TCL1 expression Genes, chromosomes & cancer Medium 11241786
2002 Sp1 transcription factor mediates transactivation of the TCL1 core promoter; three specific Sp1-binding sites within 300 bp of the transcriptional start site are required; mutation of these sites significantly represses TCL1 reporter expression; four transcriptional start sites 24–30 bp downstream of a TATA box were mapped. 5' RACE (transcriptional start site mapping); luciferase reporter assays; Sp1 dose-dependent transactivation in Sp1-negative Drosophila SL2 cells; site-directed mutagenesis of Sp1 binding sites; EMSA (specific Sp1 binding) The Journal of biological chemistry High 12421830
2006 TCL1 binds the RNase PH repeat domains of PNPase exoribonuclease through its AKT interaction domain; this interaction does not affect PNPase RNA-degrading activity. Co-immunoprecipitation identifying TCL1–PNPase complex; in vitro RNA degradation assay; computational docking models Cancer letters Medium 16934922
2012 TCL1 associates with the XBP-1 transcription factor and activates the IRE-1/XBP-1 ER stress pathway; TCL1 overexpression causes dysregulated expression of transcription factors Pax5, IRF4, Blimp-1, and AID; TCL1-overexpressing CLL cells show increased membrane-bound IgM and altered N-linked glycosylation of Igα and Igβ. Co-immunoprecipitation (TCL1–XBP-1); gene expression analysis; Western blot; IRE-1/XBP-1 pathway inhibitor experiments in vitro and in vivo mouse model Blood Medium 22692508
2013 ROR1 forms a complex with TCL1 in CLL B cells (identified by immune-precipitation and mass spectrometry); ROR1×TCL1 double-transgenic leukemia B cells have higher phospho-AKT than TCL1-only leukemia cells; anti-ROR1 mAb treatment reduces ROR1 down-modulation and phospho-AKT levels. Immunoprecipitation and mass spectrometry; Western blot for phospho-AKT; transgenic mouse crosses; anti-ROR1 mAb treatment experiments Proceedings of the National Academy of Sciences of the United States of America Medium 24379361
2015 miR-3676 targets three consecutive 28-bp repeats within the 3'UTR of TCL1 and potently inhibits TCL1 expression; miR-3676 is significantly down-regulated in multiple CLL subtypes; two identified germ-line mutations in miR-3676 from CLL samples are loss-of-function mutations that relieve TCL1 repression. 3'UTR reporter assays; miR-3676 expression quantification in CLL patient samples; sequencing of 539 CLL samples; loss-of-function mutagenesis of miR-3676 Proceedings of the National Academy of Sciences of the United States of America Medium 25646413
2011 TCL1 represses PTPROt expression by altering c-Fos expression and c-Jun activation state, thereby inhibiting AP-1-driven transcription of the PTPROt promoter; PTPROt is significantly reduced in TCL1 transgenic mouse B cells as early as 7 weeks. Luciferase reporter assays for PTPROt promoter; AP-1 overexpression and knockdown; ChIP for c-Fos and c-Jun at PTPROt promoter; Western blot and qRT-PCR in transgenic mouse B cells Blood Medium 22001392
2017 KLF4-induced TCL1 directs a metabolic shift from oxidative phosphorylation to glycolysis during iPSC reprogramming via a two-pronged mechanism: TCL1 activates AKT to enhance glycolysis and counteracts PNPase to diminish oxidative phosphorylation. Sendai virus-based KLF4-dependent reprogramming screen; KLF4 target gene identification; metabolic flux measurements (OCR/ECAR); TCL1 knockdown/overexpression; AKT inhibition; PNPase interaction assays Stem cell reports Medium 28262547
2009 EBV LMP1 down-regulates TCL1 expression by inducing miR-29b through its CTAR1 and CTAR2 activation domains; LMP1-mediated TCL1 repression is dependent on p38 MAPK signaling; miR-29b LNA antisense re-constitutes TCL1 expression in LMP1-expressing cells. miR profiling of LMP1 transfectants; LNA antisense oligonucleotide rescue experiments; pharmacological inhibitors of p38/MAPK pathway; qRT-PCR for pri-miR-29b1-a cluster Oncogene Medium 19966860
2023 Introduction of TET2 or ASXL1 mutations (but not DNMT3A) leads to TCL1A protein expression and expansion of HSCs in vitro; forced expression of TCL1A promotes human HSC expansion in vitro and mouse HSC expansion in vivo; a protective inherited polymorphism in the TCL1A promoter restricts TCL1A expression and reduces expansion of TET2-, ASXL1-, SF3B1-, and SRSF2-mutated clones but not DNMT3A-mutated clones; experimental TCL1A knockdown reduces mutant HSC expansion. GWAS of clonal haematopoiesis expansion rates; TCL1A forced expression in human and mouse HSCs; lentiviral TCL1A knockdown; in vitro HSC expansion assays; in vivo mouse HSC transplantation Nature High 37046083
2020 Enforced TCL1A enhances phospho-activation of TCR kinases, second-messenger generation, and JAK/STAT or NFAT transcriptional responses in T-PLL cells; TCL1A lowers the input threshold for IL-2 secretion in response to TCR stimulation; TCL1A is linked to resistance of T-PLL cells to activation- and FAS-induced cell death. Forced TCL1A expression in T-cell lines; phospho-flow cytometry for TCR kinases; NFAT/JAK-STAT reporter assays; TCR-defined and CAR-T cell leukemogenesis experiments in mice; primary T-PLL phenotyping Blood Medium 33301031
1994 TCL1 protein is a 14 kDa product present in the microsomal fraction of expressing cells, as determined by cell fractionation and confirmed by confocal microscopy. Bacterial expression of TCL1 ORF; antisera generation; Western blot; cell fractionation; confocal microscopy Cancer research Medium 7987816
2002 TCL1 participates in early embryonic cleavage; maternally derived TCL1 shuttles between nuclei and cortical regions in a cell-cycle-dependent manner in early embryos; absence of TCL1 impairs embryo cleavage and morula development, particularly in vitro. Analysis of Tcl1-deficient mice; immunofluorescence of wild-type embryos at first three mitotic cycles; in vitro embryo culture and development scoring Proceedings of the National Academy of Sciences of the United States of America Medium 12181493
2004 TCL1 is required for normal B and T lymphocyte development: Tcl1-deficient mice show compromised B lymphopoiesis at the pre-B cell stage, impaired T-cell development at the CD4+CD8+ thymocyte stage, increased thymocyte susceptibility to anti-CD3ε-induced apoptosis, reduced splenic follicular and GC B cells, and impaired IgG1/IgG2b antibody responses to T-dependent antigens. Analysis of Tcl1-knockout mice; flow cytometry of lymphoid compartments; anti-CD3ε-induced apoptosis assay; immunization with T-dependent antigen and antibody ELISA Blood High 15479728
2015 TCL1 levels and kinetics of TCL1–AKT co-recruitment to BCR membrane activation complexes (which include kinases LYN, SYK, ZAP70, and PKC) predict the degree of AKT phospho-activation and proliferative response to BCR stimulation in CLL; high TCL1 levels are associated with aggressive disease features. Co-immunoprecipitation of BCR activation complexes from primary CLL cells; flow cytometry for phospho-AKT; correlation with in vitro BCR stimulation growth kinetics across 70 CLL cases Blood Medium 19770358

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Human chronic lymphocytic leukemia modeled in mouse by targeted TCL1 expression. Proceedings of the National Academy of Sciences of the United States of America 541 12011454
2006 Tcl1 expression in chronic lymphocytic leukemia is regulated by miR-29 and miR-181. Cancer research 489 17178851
2000 Tcl1 enhances Akt kinase activity and mediates its nuclear translocation. Proceedings of the National Academy of Sciences of the United States of America 300 10716693
2000 The protooncogene TCL1 is an Akt kinase coactivator. Molecular cell 275 10983986
1994 Identification of the TCL1 gene involved in T-cell malignancies. Proceedings of the National Academy of Sciences of the United States of America 221 7809072
2016 Mosaic loss of chromosome Y is associated with common variation near TCL1A. Nature genetics 157 27064253
2006 B cell receptors in TCL1 transgenic mice resemble those of aggressive, treatment-resistant human chronic lymphocytic leukemia. Proceedings of the National Academy of Sciences of the United States of America 142 16864779
2003 TCL1 expression in plasmacytoid dendritic cells (DC2s) and the related CD4+ CD56+ blastic tumors of skin. Blood 129 12576313
1998 Deregulated expression of TCL1 causes T cell leukemia in mice. Proceedings of the National Academy of Sciences of the United States of America 127 9520462
2006 TCL1 shows a regulated expression pattern in chronic lymphocytic leukemia that correlates with molecular subtypes and proliferative state. Leukemia 125 16341048
2010 The Syk inhibitor fostamatinib disodium (R788) inhibits tumor growth in the Eμ- TCL1 transgenic mouse model of CLL by blocking antigen-dependent B-cell receptor signaling. Blood 124 20716772
2014 The expressions of stem cell markers: Oct4, Nanog, Sox2, nucleostemin, Bmi, Zfx, Tcl1, Tbx3, Dppa4, and Esrrb in bladder, colon, and prostate cancer, and certain cancer cell lines. Anatomy & cell biology 121 24693477
2006 Characterization of the TCL-1 transgenic mouse as a preclinical drug development tool for human chronic lymphocytic leukemia. Blood 113 16670263
2013 PTEN antagonises Tcl1/hnRNPK-mediated G6PD pre-mRNA splicing which contributes to hepatocarcinogenesis. Gut 110 24352616
2009 E(mu)-TCL1 mice represent a model for immunotherapeutic reversal of chronic lymphocytic leukemia-induced T-cell dysfunction. Proceedings of the National Academy of Sciences of the United States of America 110 19332800
2000 Regulation of TCL1 expression in B- and T-cell lymphomas and reactive lymphoid tissues. Cancer research 106 10786666
2015 Mechanisms of PD-L1/PD-1-mediated CD8 T-cell dysfunction in the context of aging-related immune defects in the Eµ-TCL1 CLL mouse model. Blood 102 25979947
2023 Aberrant activation of TCL1A promotes stem cell expansion in clonal haematopoiesis. Nature 98 37046083
2010 Diagnostic utility of novel stem cell markers SALL4, OCT4, NANOG, SOX2, UTF1, and TCL1 in primary mediastinal germ cell tumors. The American journal of surgical pathology 96 20410807
2005 The TCL1 family of oncoproteins: co-activators of transformation. Nature reviews. Cancer 95 16056259
2007 High TCL1 expression and intact T-cell receptor signaling define a hyperproliferative subset of T-cell prolymphocytic leukemia. Blood 93 17890451
2002 Dysregulated TCL1 promotes multiple classes of mature B cell lymphoma. Proceedings of the National Academy of Sciences of the United States of America 92 12381789
2001 Differential regulation of Akt kinase isoforms by the members of the TCL1 oncogene family. The Journal of biological chemistry 92 11707444
2018 Actionable perturbations of damage responses by TCL1/ATM and epigenetic lesions form the basis of T-PLL. Nature communications 90 29449575
2008 Tcl1 functions as a transcriptional regulator and is directly involved in the pathogenesis of CLL. Proceedings of the National Academy of Sciences of the United States of America 87 19064921
2009 High TCL1 levels are a marker of B-cell receptor pathway responsiveness and adverse outcome in chronic lymphocytic leukemia. Blood 84 19770358
2002 TCL1 participates in early embryonic development and is overexpressed in human seminomas. Proceedings of the National Academy of Sciences of the United States of America 84 12181493
2011 Development of CLL in the TCL1 transgenic mouse model is associated with severe skewing of the T-cell compartment homologous to human CLL. Leukemia 83 21606964
2004 TCL1 and CLA expression in agranular CD4/CD56 hematodermic neoplasms (blastic NK-cell lymphomas) and leukemia cutis. American journal of clinical pathology 80 15323148
2013 ROR1 can interact with TCL1 and enhance leukemogenesis in Eμ-TCL1 transgenic mice. Proceedings of the National Academy of Sciences of the United States of America 79 24379361
2004 Inhibition of Akt kinase activity by a peptide spanning the betaA strand of the proto-oncogene TCL1. The Journal of biological chemistry 75 15459205
2002 Identification of Akt association and oligomerization domains of the Akt kinase coactivator TCL1. Molecular and cellular biology 75 11839817
2001 The role of TCL1 in human T-cell leukemia. Oncogene 73 11607815
2009 PKCbeta is essential for the development of chronic lymphocytic leukemia in the TCL1 transgenic mouse model: validation of PKCbeta as a therapeutic target in chronic lymphocytic leukemia. Blood 72 19168795
2015 TCL1 targeting miR-3676 is codeleted with tumor protein p53 in chronic lymphocytic leukemia. Proceedings of the National Academy of Sciences of the United States of America 70 25646413
1993 Chromosome walking on the TCL1 locus involved in T-cell neoplasia. Proceedings of the National Academy of Sciences of the United States of America 68 8415691
2006 Effect of rapamycin on mouse chronic lymphocytic leukemia and the development of nonhematopoietic malignancies in Emu-TCL1 transgenic mice. Cancer research 63 16424025
2012 Overexpression of TCL1 activates the endoplasmic reticulum stress response: a novel mechanism of leukemic progression in mice. Blood 62 22692508
2001 TCL1 is activated by chromosomal rearrangement or by hypomethylation. Genes, chromosomes & cancer 59 11241786
2012 Tcl1 protein functions as an inhibitor of de novo DNA methylation in B-cell chronic lymphocytic leukemia (CLL). Proceedings of the National Academy of Sciences of the United States of America 58 22308499
2012 Aromatase inhibitors, estrogens and musculoskeletal pain: estrogen-dependent T-cell leukemia 1A (TCL1A) gene-mediated regulation of cytokine expression. Breast cancer research : BCR 58 22405131
2007 Proto-oncogene TCL1: more than just a coactivator for Akt. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 58 17360849
1996 Partial characterization of an immortalized human trophoblast cell-line, TCL-1, which possesses a CSF-1 autocrine loop. Placenta 57 8730883
2015 Two types of BCR interactions are positively selected during leukemia development in the Eμ-TCL1 transgenic mouse model of CLL. Blood 55 25564405
1995 TCL1 oncogene activation in preleukemic T cells from a case of ataxia-telangiectasia. Blood 51 7662982
1994 Characterization and localization of the TCL-1 oncogene product. Cancer research 51 7987816
2013 Loss of p53 and altered miR15-a/16-1MCL-1 pathway in CLL: insights from TCL1-Tg:p53(-/-) mouse model and primary human leukemia cells. Leukemia 50 23608884
2009 Epstein-Barr virus encoded LMP1 downregulates TCL1 oncogene through miR-29b. Oncogene 50 19966860
2008 Characteristic expression patterns of TCL1, CD38, and CD44 identify aggressive lymphomas harboring a MYC translocation. The American journal of surgical pathology 50 18162778
1997 TCL1 is overexpressed in patients affected by adult T-cell leukemias. Cancer research 50 9407948
1999 Genomic analysis of human and mouse TCL1 loci reveals a complex of tightly clustered genes. Proceedings of the National Academy of Sciences of the United States of America 48 10588720
2009 Chronic lymphocytic leukemia of Emu-TCL1 transgenic mice undergoes rapid cell turnover that can be offset by extrinsic CD257 to accelerate disease progression. Blood 45 19755673
2008 TCL1A expression delineates biological and clinical variability in B-cell lymphoma. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 45 18820675
2011 Tcl1 interacts with Atm and enhances NF-κB activation in hematologic malignancies. Blood 43 22065599
2003 Infection of HHV-8+ primary effusion lymphoma cells with a recombinant Epstein-Barr virus leads to restricted EBV latency, altered phenotype, and increased tumorigenicity without affecting TCL1 expression. Blood 43 12969959
2016 TCL1 transgenic mouse model as a tool for the study of therapeutic targets and microenvironment in human B-cell chronic lymphocytic leukemia. Cell death & disease 42 26821067
2013 Autoantigen can promote progression to a more aggressive TCL1 leukemia by selecting variants with enhanced B-cell receptor signaling. Proceedings of the National Academy of Sciences of the United States of America 42 23550156
2004 Structural basis for the co-activation of protein kinase B by T-cell leukemia-1 (TCL1) family proto-oncoproteins. The Journal of biological chemistry 42 15169787
2015 The PI3K/mTOR inhibitor PF-04691502 induces apoptosis and inhibits microenvironmental signaling in CLL and the Eµ-TCL1 mouse model. Blood 39 25957390
2006 EBNA2 interferes with the germinal center phenotype by downregulating BCL6 and TCL1 in non-Hodgkin's lymphoma cells. Journal of virology 39 17151114
2021 Combined ibrutinib and venetoclax treatment vs single agents in the TCL1 mouse model of chronic lymphocytic leukemia. Blood advances 37 34555843
2015 Chronic lymphocytic leukaemia induces an exhausted T cell phenotype in the TCL1 transgenic mouse model. British journal of haematology 37 25940792
2021 Combining ibrutinib and checkpoint blockade improves CD8+ T-cell function and control of chronic lymphocytic leukemia in Em-TCL1 mice. Haematologica 36 32139435
2017 A Role for KLF4 in Promoting the Metabolic Shift via TCL1 during Induced Pluripotent Stem Cell Generation. Stem cell reports 36 28262547
1998 Expression of the TCL1 gene at 14q32 in B-cell malignancies but not in adult T-cell leukemia. Japanese journal of cancer research : Gann 36 9738977
2012 Stromal cells modulate TCL1 expression, interacting AP-1 components and TCL1-targeting micro-RNAs in chronic lymphocytic leukemia. Leukemia 35 22460735
1997 The murine Tcl1 oncogene: embryonic and lymphoid cell expression. Oncogene 35 9285687
2004 Impaired T- and B-cell development in Tcl1-deficient mice. Blood 34 15479728
1998 Crystal structure of MTCP-1: implications for role of TCL-1 and MTCP-1 in T cell malignancies. Proceedings of the National Academy of Sciences of the United States of America 33 9520380
1996 Expression of either the TCL1 oncogene, or transcripts from its homologue MTCP1/c6.1B, in leukaemic and non-leukaemic T cells from ataxia telangiectasia patients. Oncogene 33 8570215
2010 CD5+CD23+ leukemic cell populations in TCL1 transgenic mice show significantly increased proliferation and Akt phosphorylation. Leukemia 32 20357824
2009 Epstein-Barr virus nuclear protein 3C domains necessary for lymphoblastoid cell growth: interaction with RBP-Jkappa regulates TCL1. Journal of virology 31 19776126
2020 HDAC6 Inhibition Alleviates CLL-Induced T-Cell Dysfunction and Enhances Immune Checkpoint Blockade Efficacy in the Eμ-TCL1 Model. Frontiers in immunology 30 33329575
2002 A modeled hydrophobic domain on the TCL1 oncoprotein mediates association with AKT at the cytoplasmic membrane. Biochemistry 30 12009899
2020 Noncanonical effector functions of the T-memory-like T-PLL cell are shaped by cooperative TCL1A and TCR signaling. Blood 29 33301031
2018 T-Cell Leukemia/Lymphoma 1 (TCL1): An Oncogene Regulating Multiple Signaling Pathways. Frontiers in oncology 28 30151355
2018 Exome sequencing of the TCL1 mouse model for CLL reveals genetic heterogeneity and dynamics during disease development. Leukemia 28 30262843
2008 Incidence of TCR and TCL1 gene translocations and isochromosome 7q in peripheral T-cell lymphomas using fluorescence in situ hybridization. American journal of clinical pathology 28 18628085
2012 TCL1: a shared tumor-associated antigen for immunotherapy against B-cell lymphomas. Blood 27 22645177
2010 Pluripotent reprogramming of fibroblasts by lentiviral mediated insertion of SOX2, C-MYC, and TCL-1A. Stem cells and development 27 20504151
2007 TCL1 in B-cell tumors retains its normal b-cell pattern of regulation and is a marker of differentiation stage. The American journal of surgical pathology 27 17592280
2015 miR-181b as a therapeutic agent for chronic lymphocytic leukemia in the Eµ-TCL1 mouse model. Oncotarget 25 26090867
2013 Genomic profiling reveals the potential role of TCL1A and MDR1 deficiency in chemotherapy-induced cardiotoxicity. International journal of biological sciences 25 23630447
2013 Chronic lymphocytic leukemia disease progression is accelerated by APRIL-TACI interaction in the TCL1 transgenic mouse model. Blood 24 24100449
2000 Activation of the TCL1 protein in B cell lymphomas. Pathology international 24 10792782
2019 Polycyclic aromatic hydrocarbons exposure and their joint effects with age, smoking, and TCL1A variants on mosaic loss of chromosome Y among coke-oven workers. Environmental pollution (Barking, Essex : 1987) 23 31818624
2002 Sp1 transactivation of the TCL1 oncogene. The Journal of biological chemistry 23 12421830
2014 T-cell prolymphocytic leukemia frequently shows cutaneous involvement and is associated with gains of MYC, loss of ATM, and TCL1A rearrangement. The American journal of surgical pathology 22 25310835
2013 Accelerated progression of chronic lymphocytic leukemia in Eμ-TCL1 mice expressing catalytically inactive RAG1. Blood 21 23502221
2012 Diagnostic utility of CD117, CD133, SALL4, OCT4, TCL1 and glypican-3 in malignant germ cell tumors of the ovary. The journal of obstetrics and gynaecology research 21 22448662
2007 TORC2 regulates germinal center repression of the TCL1 oncoprotein to promote B cell development and inhibit transformation. Proceedings of the National Academy of Sciences of the United States of America 21 17548807
2006 The TCL1 oncoprotein binds the RNase PH domains of the PNPase exoribonuclease without affecting its RNA degrading activity. Cancer letters 21 16934922
2019 p66Shc deficiency in the Eμ-TCL1 mouse model of chronic lymphocytic leukemia enhances leukemogenesis by altering the chemokine receptor landscape. Haematologica 20 30819907
2012 Intracytoplasmic detection of TCL1--but not ILT7-by flow cytometry is useful for blastic plasmacytoid dendritic cell leukemia diagnosis. Cytometry. Part A : the journal of the International Society for Analytical Cytology 20 22674796
2011 Nutlin-3 downregulates the expression of the oncogene TCL1 in primary B chronic lymphocytic leukemic cells. Clinical cancer research : an official journal of the American Association for Cancer Research 20 21753157
2011 AP-1 elements and TCL1 protein regulate expression of the gene encoding protein tyrosine phosphatase PTPROt in leukemia. Blood 20 22001392
1999 Identification of the TCL1/MTCP1-like 1 (TML1) gene from the region next to the TCL1 locus. Cancer research 20 10344735
2007 The TCL1 oncoprotein inhibits activation-induced cell death by impairing PKCtheta and ERK pathways. Blood 19 17846228
2005 TCL1 expression and Epstein-Barr virus status in pediatric Burkitt lymphoma. American journal of clinical pathology 19 16146820
2015 The regulatory interaction of EVI1 with the TCL1A oncogene impacts cell survival and clinical outcome in CLL. Leukemia 17 25936528

Missed literature

Know a paper Affinage missed for TCL1A? Flag it for the maintainers and the community.

No submissions yet.