Affinage

HLF

Hepatic leukemia factor · UniProt Q16534

Round 2 corrected
Length
295 aa
Mass
33.2 kDa
Annotated
2026-04-28
130 papers in source corpus 54 papers cited in narrative 54 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HLF is a PAR-subfamily basic leucine zipper (bZIP) transcription factor that binds the consensus sequence 5'-GTTACGTAAT-3' as a homodimer or heterodimer with DBP and TEF, activating target genes through a highly conserved transactivation domain (THAD) in liver, kidney, brain, and hematopoietic stem cells (PMID:1386162, PMID:8065331, PMID:7556072, PMID:8639829). In normal physiology, HLF marks and maintains hematopoietic stem cell identity from embryonic specification onward, operates downstream of MEIS1 and within an Evi-1/HLF axis to control HSC self-renewal and oxidative stress resistance, and cooperates with DBP and TEF to drive circadian xenobiotic detoxification in liver and kidney (PMID:34499717, PMID:31076455, PMID:25740828, PMID:16814730). In disease contexts, HLF promotes hepatic stellate cell activation and liver fibrosis through an HLF/IL-6/STAT3 feedforward circuit, transactivates diverse oncogenic targets (c-Jun, GGT1, YAP1, FZD4, TFEB, IL-6R) in solid tumors, and suppresses metastasis in ccRCC via LPXN/Paxillin-mediated cytoskeletal regulation when not epigenetically silenced by BRG1 (PMID:28754776, PMID:31118247, PMID:34991659, PMID:40473600, PMID:40779629). The t(17;19) chromosomal translocation fuses E2A transactivation domains to the HLF bZIP domain, creating the E2A-HLF oncoprotein that drives B-lineage acute lymphoblastic leukemia by blocking apoptosis downstream of p53 and activating survival targets including SLUG, LMO2, Survivin, and MYC through hijacking of HLF-bound enhancers (PMID:1386162, PMID:8700228, PMID:10518215, PMID:20519628, PMID:31735627).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1992 High

    Cloning of HLF revealed it as a PAR bZIP transcription factor and identified the t(17;19)-generated E2A-HLF chimera as the molecular basis of a subset of B-lineage ALL, establishing the gene's dual identity in normal tissue-specific transcription and leukemogenesis.

    Evidence Molecular cloning, Northern blot, chimeric transcript sequencing, gel mobility shift assays showing homodimeric and heterodimeric DNA binding

    PMID:1386162 PMID:1516826

    Open questions at the time
    • Wild-type HLF function in hematopoiesis unknown
    • Downstream targets of E2A-HLF unidentified
    • Structural basis of dimerization preference unresolved
  2. 1995 High

    Characterization of the HLF consensus binding site (5'-GTTACGTAAT-3'), identification of two isoforms from alternative promoters with distinct circadian amplitudes and target gene preferences, and mapping of the conserved THAD transactivation domain established the molecular toolkit for HLF-mediated transcription.

    Evidence In vitro binding site selection, reporter assays across cell types, alternative promoter mapping with CUG initiation, GAL4 fusion deletion analysis

    PMID:7556072 PMID:8065331 PMID:8639829

    Open questions at the time
    • Crystal structure of HLF bZIP domain lacking
    • Cofactors recruited by THAD unknown
    • Chromatin-level target gene regulation not explored
  3. 1996 High

    Demonstration that E2A-HLF blocks apoptosis (both IL-3 withdrawal and p53-mediated) rather than promoting proliferation resolved a fundamental question about the oncogenic mechanism, showing the chimera sustains cell survival.

    Evidence Dominant-negative E2A-HLF suppression in t(17;19) leukemia cells, IL-3 deprivation and p53-mediated apoptosis assays in pro-B cells

    PMID:8700228

    Open questions at the time
    • Downstream survival effectors of E2A-HLF not yet identified
    • Mechanism by which survival is uncoupled from growth unclear
  4. 1999 High

    Identification of SLUG as an E2A-HLF-activated antiapoptotic effector, demonstration that E2A-HLF transforms through homodimeric (gain-of-function) rather than dominant-negative binding, and in vivo transgenic modeling showing E2A-HLF disrupts lymphoid development requiring additional cooperating events, collectively defined the leukemogenic pathway.

    Evidence SLUG identification and IL-3 withdrawal rescue, leucine zipper mutagenesis separating homo- from heterodimer function, E2A-HLF transgenic mouse with lymphoid defects and T-ALL

    PMID:10216071 PMID:10518215 PMID:9032268

    Open questions at the time
    • Direct promoter binding by E2A-HLF to SLUG not shown
    • Full repertoire of cooperating mutations unknown
    • Wild-type HLF role in normal B-cell development unaddressed
  5. 2001 High

    Discovery that E2A-HLF activates Groucho-related corepressors and can function through protein-protein interactions independent of direct DNA binding expanded the mechanistic model beyond simple sequence-specific transactivation.

    Evidence RDA in zinc-inducible FL5.12 pro-B cell system, DNA-binding-disabled E2A-HLF mutant retaining survival activity

    PMID:11486032

    Open questions at the time
    • Identity of protein partners mediating DNA-binding-independent activity unknown
    • Groucho targets downstream of E2A-HLF not defined
  6. 2006 High

    Triple knockout of all three PAR bZIP factors (DBP/TEF/HLF) revealed their collective role in circadian xenobiotic detoxification, providing the first in vivo physiological function for HLF outside of hematopoiesis and cancer.

    Evidence PAR bZIP triple knockout mouse with liver/kidney transcriptome profiling and xenobiotic hypersensitivity

    PMID:16814730

    Open questions at the time
    • Individual contribution of HLF vs. DBP vs. TEF to detoxification gene regulation unresolved
    • Cardiovascular phenotype later found in triple KO not yet attributed to specific PAR factor
  7. 2010 High

    Identification of LMO2 and BCL-2 as direct E2A-HLF targets whose combined expression recapitulates E2A-HLF immortalization, and ZNF521 as a cooperating gene, defined the minimal oncogenic circuitry for E2A-HLF-driven B-ALL.

    Evidence ChIP/reporter for LMO2, shRNA and pharmacological BCL-2 inhibition, retroviral insertional mutagenesis identifying ZNF521 in E2A-HLF knock-in mice

    PMID:20062079 PMID:20519628 PMID:21072044

    Open questions at the time
    • Whether LMO2/BCL-2 sufficiency applies in human primary leukemia cells untested
    • Mechanism of ZNF521 cooperation with E2A-HLF unclear
  8. 2015 High

    Placing HLF downstream of MEIS1 in MLL-fusion leukemia, where HLF rescues oxidative stress and leukemia maintenance in Meis1-deficient cells, established HLF as a functional effector of the MEIS1-dependent stem cell program beyond the t(17;19) context.

    Evidence Inducible Meis1 knockout crossed with MLL-AF9 knock-in, ChIP-confirmed MEIS1 binding to HLF locus, HLF rescue of leukemia in vivo

    PMID:25740828

    Open questions at the time
    • Direct transcriptional targets of wild-type HLF in leukemia maintenance undefined
    • Whether HLF regulates ROS through xenobiotic enzymes or other pathways unknown
  9. 2017 High

    Discovery of the HLF/IL-6/STAT3 feedforward circuit in hepatic stellate cells, validated by HLF-knockout mice with attenuated fibrosis, established the first non-hematopoietic, non-circadian disease mechanism for wild-type HLF.

    Evidence HLF-knockout mouse model, primary HSC isolation, LX2 human HSC line, HLF gain/loss-of-function with IL-6/STAT3 pathway measurement

    PMID:28754776

    Open questions at the time
    • Direct HLF binding sites on the IL-6 promoter not mapped by ChIP-seq
    • Whether HLF has roles in other fibrotic organs beyond liver unknown
  10. 2019 High

    Genome-wide ChIP-seq of endogenous TCF3-HLF revealed it hijacks HLF binding sites at HSC/myeloid super-enhancers to activate MYC and cooperates with ERG and EP300, while parallel studies showed HLF marks the entire HSC developmental continuum from arterial endothelium through the Evi-1/HLF axis, unifying the fusion oncogene's mechanism with normal HSC biology.

    Evidence ChIP-seq, CRISPRi, EP300 inhibitor treatment, Hlf-tdTomato knock-in reporter mouse, in vivo transplantation, Evi-1/Hlf axis characterization

    PMID:31076455 PMID:31118247 PMID:31735627

    Open questions at the time
    • Whether EP300 inhibitors have therapeutic efficacy in patients with t(17;19) ALL untested
    • How HLF binding site specificity differs between HSCs and leukemia cells unresolved
  11. 2021 High

    Genomic HLF reporter strategies and lineage tracing in human and mouse systems confirmed HLF as one of the most specific transcriptional markers defining HSC identity, with HLF+ cells comprising all long-term repopulating stem cell activity.

    Evidence HLF-tdTomato reporter, HLF-CreER lineage tracing at E9.5, serial transplantation, single-cell transcriptomics

    PMID:34499717 PMID:34589491

    Open questions at the time
    • Functional consequences of HLF loss specifically in adult HSCs (single-gene knockout) not reported
    • Whether HLF is instructive or merely correlative for HSC identity unresolved
  12. 2022 High

    In solid tumors, HLF was shown to transactivate GGT1 to confer ferroptosis resistance in TNBC downstream of macrophage-derived TGF-β1 signaling, revealing a cancer-type-specific mechanism distinct from its leukemic or hepatic roles.

    Evidence ChIP/reporter for HLF→GGT1, ferroptosis assays, TNBC xenograft with cytokine pathway inhibition

    PMID:34991659

    Open questions at the time
    • Whether HLF-mediated ferroptosis resistance is generalizable to other cancer types unknown
    • Direct structural basis of HLF target gene selectivity across tissues unresolved
  13. 2024 High

    An in vivo CRISPR screen identified HLF as a metastasis suppressor in ccRCC, epigenetically silenced by BRG1, that restrains invasion through LPXN/Paxillin-mediated cytoskeletal regulation, establishing a tumor-suppressive role directly opposing its oncogenic functions in other contexts.

    Evidence Genome-wide in vivo CRISPR screen, HLF overexpression/depletion in metastasis assays, BRG1 ChIP, LPXN/Paxillin pathway characterization

    PMID:40473600

    Open questions at the time
    • How the same transcription factor acts as oncogene vs. tumor suppressor in different tissues remains mechanistically unexplained
    • Whether BRG1-mediated silencing of HLF occurs in cancers beyond ccRCC untested
  14. 2025 High

    Identification of TFEB and IL-6R as direct HLF targets in gallbladder cancer stem cells, driving autophagy-dependent drug resistance and PD-L1-mediated immune evasion, extended HLF's target repertoire to immune-modulatory and autophagy pathways.

    Evidence CUT&Tag/ChIP for HLF→TFEB/IL-6R, xenograft/PDX models, CD8+ T cell depletion experiments

    PMID:40779629

    Open questions at the time
    • Whether HLF-TFEB axis operates in non-cancer stem cells unknown
    • Therapeutic targeting of HLF itself remains unexplored

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: how HLF exerts opposing oncogenic versus tumor-suppressive functions across tissue contexts, what the functional consequences of isolated HLF loss are in adult HSCs, and whether HLF can be directly targeted therapeutically.
  • No conditional single-gene HLF knockout in adult HSCs reported
  • No crystal structure of HLF bZIP domain available
  • Tissue-specific cofactor interactions determining target gene selectivity uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 9 GO:0003677 DNA binding 4
Localization
GO:0005634 nucleus 1
Pathway
R-HSA-74160 Gene expression (Transcription) 7 R-HSA-5357801 Programmed Cell Death 6 R-HSA-1643685 Disease 5 R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 4 R-HSA-9612973 Autophagy 1
Partners
DBPE2AEP300ERGMEIS1STAT3TEF

Evidence

Reading pass · 54 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1992 HLF (hepatic leukemia factor) encodes a PAR-subfamily basic leucine zipper (bZIP) transcription factor normally expressed in liver and kidney; the t(17;19) chromosomal translocation fuses the E2A transactivation domain to the HLF bZIP domain, creating the chimeric E2A-HLF oncoprotein in acute B-lineage leukemia. Molecular cloning, Northern blot, chimeric transcript sequencing Science High 1386162 1516826
1992 Wild-type HLF binds DNA specifically as a homodimer or heterodimer with other PAR family factors (DBP, TEF); the E2A-HLF fusion protein has markedly impaired homodimerization but retains heterodimeric DNA binding with PAR proteins, suggesting a novel mechanism for leukemogenic conversion. Gel mobility shift assay, in vitro DNA-binding, dimerization assays Genes & development High 1516826
1994 HLF and E2A-HLF selectively bind the consensus DNA sequence 5'-GTTACGTAAT-3' with high affinity; E2A-HLF chimeras show reduced tolerance for sequence deviations due to loss of an HLF ancillary DNA-binding domain, and both activate transcription from consensus-site reporter genes in lymphoid and non-lymphoid cells, but E2A-HLF can competitively inhibit wild-type PAR protein activation at suboptimal binding sites. In vitro binding site selection, gel shift assay, transient transfection reporter assays Molecular and cellular biology High 8065331
1995 The rat HLF gene is transcribed from two alternative promoters (alpha and beta) producing a 43 kDa protein (HLF43, abundant in brain/liver/kidney) and a novel 36 kDa protein (HLF36, liver-specific, initiated from a CUG codon); the two isoforms accumulate with different circadian amplitudes and have distinct liver-specific promoter preferences in transfection experiments—HLF43 preferentially activates the cholesterol 7α-hydroxylase promoter while HLF36 preferentially activates the albumin promoter. Alternative promoter characterization, CUG-initiation identification, Western blot, transfection reporter assays, circadian expression analysis The EMBO journal High 7556072
1995 E2A-HLF-mediated cell transformation requires both the bipartite E2A transactivation domains and the HLF leucine zipper dimerization domain; mutants lacking either the E2A activation domains or the HLF leucine zipper fail to transform NIH 3T3 cells or support anchorage-independent growth and tumor formation in nude mice. NIH 3T3 transformation assay, soft agar colony formation, nude mouse tumor xenograft, deletion mutagenesis Molecular and cellular biology High 7760820
1996 The E2A-HLF chimeric oncoprotein reverses apoptosis in murine pro-B lymphocytes, blocking both IL-3 withdrawal-induced and p53-mediated cell death; dominant-negative suppression of E2A-HLF in human t(17;19) leukemia cells rapidly induced apoptosis, demonstrating that the oncoprotein promotes cell survival rather than growth. Dominant-negative suppressor expression, IL-3 deprivation apoptosis assay, p53-mediated apoptosis assay in pro-B cells Nature High 8700228
1996 TEF and HLF share identical DNA-binding consensus sequences (5'-GTTACGTAAT-3') and possess a highly conserved ~40 amino acid transcriptional activation domain (THAD) whose deletion completely abrogates transcriptional activity in both mammalian cells and yeast; this THAD represents one of the most evolutionarily conserved transcriptional activation domains identified. Binding site selection assay, GAL4 fusion deletion mapping, reporter assays in mammalian cells and yeast Blood High 8639829
1997 E2A-HLF transforms cells through homodimeric binding to downstream target gene promoters (gain-of-function), not through dominant-negative interference with wild-type PAR proteins; leucine zipper mutants that can homodimerize but cannot heterodimerize with HLF/TEF/DBP retain full transforming activity, and transformation requires intact E2A activator regions. Leucine zipper domain mutagenesis (extended helix, charged residue alterations), NIH 3T3 soft agar transformation assay Molecular and cellular biology High 9032268
1997 E2A-PBX1 and E2A-HLF chimeric oncoproteins concentrate within discrete spherical nuclear domains (chimeric-E2A oncoprotein domains, CODs) that require protein elements from both fusion partners; wild-type E2A or PBX1 alone show diffuse nuclear distribution, indicating COD formation is a gain-of-function property of the chimera. Immunofluorescence microscopy, nuclear localization analysis, co-transfection experiments Oncogene Medium 9366523
1998 The antiapoptotic activity of E2A-HLF in IL-3-deprived pro-B cells depends critically on the E2A transactivation domains (AD1 and AD2), not on DNA binding or leucine zipper-mediated dimerization through the HLF bZIP domain; bZIP-disabled mutants retaining either E2A activation domain still extend cell survival, suggesting protein-protein interactions via the E2A N-terminus allow the chimera to act as a transcriptional cofactor. Zinc-inducible expression of E2A-HLF deletion/point mutants in FL5.12 IL-3-dependent pro-B cells, apoptosis assay upon IL-3 withdrawal Molecular and cellular biology High 9742120
1998 The E2A-HLF chimera abrogates p53-induced apoptosis in myeloid leukemia cells, acting downstream of p53 since p53-responsive genes (p21, Bax) are still normally upregulated; NFIL3, a related bZIP protein binding the same consensus site, cannot substitute for this anti-p53 function, indicating E2A-HLF has unique cell-type-specific survival properties. Temperature-sensitive p53 mutant M1 myeloid cell system, enforced E2A-HLF expression, apoptosis assay, p53-target gene expression analysis Blood High 9694729
1999 HLF and E2A-HLF transactivate the HBV enhancer II (EnII) through binding to nucleotides 1640–1663; specifically, HLF activates the core upstream regulatory sequence and predominantly stimulates pregenome RNA synthesis, while FTF activates the full enhancer; E4BP4 binding to the same site has opposing repressive effects. Yeast one-hybrid screening, transient transfection reporter assays, primer extension analysis Journal of virology Medium 10627534
1999 E2A-HLF activates expression of SLUG, a zinc-finger transcription factor of the Snail family closely related to C. elegans CES-1 antiapoptotic protein; SLUG expression is nearly as effective as Bcl-2 or Bcl-xL in promoting survival of IL-3-deprived pro-B cells, establishing SLUG as a downstream effector of E2A-HLF in blocking apoptosis. E2A-HLF-responsive gene search, SLUG identification, IL-3 withdrawal survival assay with Bcl-2/Bcl-xL comparison Molecular cell High 10518215
1999 E2A-HLF transgenic mice (lymphoid-directed expression) exhibit T-cell apoptosis, B-cell maturation arrest at an early developmental stage, and susceptibility to infection due to immunodeficiency; several transgenic mice develop T-ALL, demonstrating that E2A-HLF disrupts lymphoid development in vivo and requires additional events for full malignant transformation. Transgenic mouse model (Ig enhancer/promoter-driven E2A-HLF), TUNEL staining, flow cytometry, in vitro colony formation assay Blood High 10216071
1999 Two E2A-HLF downstream target genes were identified: ANNEXIN VIII (upregulated in t(17;19)+ leukemia cells) and SRPUL (a novel sushi-repeat protein); both transcripts decline rapidly within 8–12 hours of E2A-HLF suppression, though neither prevents apoptosis in IL-3-deprived pro-B cells, suggesting paraneoplastic rather than core survival roles. Representational difference analysis (RDA) of E2A-HLF-active vs. inactive cells, zinc-inducible dominant-negative system Blood Medium 9864177
2001 E2A-HLF activates expression of Groucho-related transcriptional corepressors (Grg2, Grg6, and indirectly Grg1, Grg4) 10–50 fold, and downregulates RUNX1 among known Groucho-interacting transcription factors; a DNA-binding-disabled E2A-HLF mutant still mediates pro-B cell survival and activates Groucho genes, suggesting the survival function operates partly through protein-protein interactions independent of direct DNA binding. Representational difference analysis, zinc-inducible E2A-HLF system in FL5.12 pro-B cells, immunoblot, DNA-binding mutant analysis Molecular and cellular biology High 11486032
2001 CREB is a cellular component of the Ces-2/E2A-HLF binding element (CBE) complex and is part of the IL-3 survival signal; IL-3 stimulation induces CREB phosphorylation at Ser133 partially via PKA; PKA activation prolongs Ba/F3 cell survival in the absence of IL-3; the bcl-2 gene promoter contains functional CRE and CBE sites required for IL-3-inducible expression. EMSA, in vitro translation/recombinant protein binding, PKA inhibitor/activator experiments, luciferase reporter assays with bcl-2 promoter mutations Molecular and cellular biology High 11416141
2001 The DBP transcriptional activation domain (TAD) is highly homologous to those of HLF and TEF; deletion of this domain completely abrogates DBP transcriptional activity; the core PAR protein TAD maps to a region of 13 amino acids in HLF (by GAL4-HLF fusion analysis); liver-specific activity is not intrinsic to the TAD but is conferred by other protein regions. GAL4 fusion deletion analysis, transient transfection reporter assays in multiple cell types, comparative sequence analysis Gene Medium 11223263
2002 E2A-Hlf expression in bone marrow B-cell progenitors induces short-lived cell clusters without sustained growth; co-expression with Bcl-2 results in sustained self-renewal of pre-B-I cells requiring stromal and IL-7 support, and induces leukemias in irradiated recipients with long latency, demonstrating that E2A-Hlf requires suppression of apoptosis (via Bcl-2) and additional mutations for full leukemogenic conversion. Retroviral transduction-transplantation, bone marrow stromal co-culture, leukemia transplantation assay Molecular and cellular biology High 12370314
2003 Annexin II expression in t(17;19)+ leukemia cells is induced by E2A-HLF and is regulated downstream of Ras/PI3K pathways activated by IL-3; E2A-HLF increases annexin II expression in IL-3-deprived cells, effectively substituting for cytokine-activated Ras signaling. Enforced E2A-HLF expression, cytokine deprivation, Ras pathway inhibitor studies, Western blot Blood Medium 15070701
2004 E4BP4 is a downstream transcriptional target of E2A-HLF in pro-B cells; E2A-HLF acts as a transcriptional activator while E4BP4 acts as a transcriptional repressor at the same DNA binding element (CBE); overexpression of E4BP4 alone cannot block apoptosis from IL-3 withdrawal, distinguishing E2A-HLF's survival function from E4BP4's activity. Tetracycline-inducible expression system in Baf-3 cells, reporter gene assays, IL-3 withdrawal apoptosis assay British journal of haematology Medium 15147370
2005 TEF (thyrotroph embryonic factor), a PAR bZIP protein related to HLF that recognizes the same DNA sequence, protects IL-3-dependent pro-B cells from apoptosis and uniquely downregulates expression of the common beta chain (βc) of cytokine receptors, causing G0/G1 arrest without apoptosis; in contrast, E2A-HLF promotes survival more efficiently but does not downregulate βc, demonstrating distinct functional properties between the two related proteins. Retroviral expression in FL5.12 cells, IL-3 withdrawal survival assay, flow cytometry cell cycle analysis, receptor expression analysis Blood Medium 15665112
2006 PAR bZIP transcription factors DBP, TEF, and HLF (which accumulate in a circadian manner in liver and kidney) collectively control expression of enzymes and regulators involved in xenobiotic detoxification, including cytochrome P450 enzymes, carboxylesterases, and CAR; triple knockout mice devoid of all three PAR bZIP factors are hypersensitive to xenobiotic compounds. PAR bZIP triple knockout mouse model, liver/kidney transcriptome comparison, xenobiotic sensitivity assays Cell metabolism High 16814730
1999 HLF and DBP form heterodimers that bind to multiple sites in the Factor VIII and Factor IX promoters with enhanced affinity compared to homodimers; HLF alone and in synergistic combination with DBP transactivates the Factor VIII and Factor IX promoters in HepG2 cells; the E2A-HLF chimera can also mediate expression from these promoters in both hepatoma and pre-B ALL cells. Transient transfection reporter assays in HepG2 cells, gel mobility shift assay demonstrating heterodimer binding DNA and cell biology Medium 10073576
2009 E2A-HLF transcriptionally upregulates Survivin expression throughout the cell cycle in t(17;19)+ ALL cells; Survivin suppression induces massive caspase-independent apoptosis involving AIF translocation from mitochondria to nucleus; AIF knockdown confers resistance to Survivin-loss-induced apoptosis, establishing that E2A-HLF promotes cell survival by maintaining Survivin to prevent AIF-mediated mitochondrial apoptosis. Dominant-negative E2A-HLF suppression, enforced E2A-HLF expression, reporter assays, counterflow centrifugal elutriation, dominant-negative Survivin, AIF knockdown, cell cycle analysis The Journal of biological chemistry High 19887369
2010 PAR bZIP triple knockout mice (DBP/TEF/HLF-null) develop cardiac hypertrophy and left ventricular dysfunction with low blood pressure, associated with low aldosterone levels and an abnormal cardiovascular response; this demonstrates a role for the PAR bZIP factors including HLF in regulating cardiovascular physiology and aldosterone production. Triple knockout mouse model, cardiac morphology analysis, blood pressure measurement, aldosterone level measurement American journal of physiology. Regulatory, integrative and comparative physiology Medium 20686175
2010 E2A-HLF aberrantly induces LMO2 expression through direct binding to a PAR transcription factor binding site in the LMO2 promoter; this induction depends on both the DNA-binding and transactivation activities of E2A-HLF; shRNA-mediated LMO2 silencing in t(17;19)-ALL cells induces apoptosis, establishing LMO2 as a critical E2A-HLF survival target. Transfection of E2A-HLF into non-t(17;19) ALL cells, promoter reporter assays with PAR-site mutations, shRNA knockdown, apoptosis assay Blood High 20519628
2010 Retroviral expression of E2A-HLF alone is sufficient to immortalize primary lymphoid progenitors; Lmo2 and Bcl-2 are identified as direct downstream target genes of E2A-HLF; co-expression of Lmo2 and Bcl-2 alone recapitulates E2A-HLF immortalization; shRNA knockdown of Lmo2 or pharmacological BCL-2 inhibition in E2A-HLF-immortalized cells severely compromises viability. Retroviral expression, real-time PCR in patient biopsies and cell lines, shRNA knockdown, BCL-2 pharmacological inhibition Leukemia High 21072044
2010 Zfp521/ZNF521 was identified as a cooperative gene required with E2A-HLF to develop acute B-lineage leukemia; retroviral insertional mutagenesis in E2A-HLF knock-in mice identified Gfi1, Ikaros, and Zfp521 as common integration sites; tumors with Zfp521 integration exclusively showed B-lineage ALL phenotype; ZNF521 is overexpressed in human t(17;19)-positive leukemic cell lines. Inducible knock-in mice, retroviral insertional mutagenesis, inverse PCR, ZNF521 expression analysis in human cell lines, double transgenic mice Oncogene High 20062079
2012 E2A-HLF transcriptionally upregulates death receptors DR4 and DR5 through direct binding to the 5' upstream region of the DR4 gene in a DNA-binding and transactivation-dependent manner; this sensitizes t(17;19)-ALL cells to TRAIL-mediated apoptosis via the extrinsic pathway, providing a potential basis for graft-versus-leukemia effects. Reporter assays with DR4 promoter regions, enforced E2A-HLF expression in non-t(17;19) cells, recombinant TRAIL apoptosis assay Leukemia Medium 22743623
2015 MEIS1 regulates HLF expression in MLL-fusion leukemia (ChIP-seq/gene expression analysis); Meis1 loss leads to increased oxidative stress and apoptosis in leukemic cells; exogenous HLF expression rescues leukemia development in Meis1-deficient cells by reversing the oxidative stress phenotype, placing HLF downstream of MEIS1 in a pathway controlling reactive oxygen species and leukemia maintenance. Inducible Meis1-knockout mice crossed with MLL-AF9 knock-in, ChIP, gene expression profiling, HLF rescue experiment, oxidative stress measurement Blood High 25740828
2015 Hlf is a genetic modifier of epilepsy caused by voltage-gated sodium channel mutations; Hlf knockout mice crossed with Scn2a(Q54) epilepsy mice show elevated seizure frequency and reduced survival; dietary pyridoxine deficiency similarly elevates seizures, and Hlf heterozygous knockout worsens survival in Scn1a(KO/+) Dravet syndrome mice, suggesting HLF modifies epilepsy severity through the pyridoxine metabolic pathway. Hlf targeted knockout mouse model, double mutant crosses with Scn2a(Q54) and Scn1a(KO/+), seizure frequency monitoring, pyridoxine-deficient diet experiment Epilepsy research Medium 26656780
2016 TCF3-HLF expression suppresses homologous recombination repair (HRR) activity by decreasing MCPH1 levels, which in turn reduces BRCA1 expression; this HRR deficiency causes synthetic lethality with PARP inhibitors, and olaparib was effective in an in vivo xenograft model of TCF3-HLF-positive leukemia. HRR activity assay, MCPH1/BRCA1 expression analysis, PARP inhibitor cytotoxicity screening, in vivo xenograft Cancer letters Medium 27894958
2016 HLF directly binds to the BS1 site of the miR-132 promoter to enhance miR-132 expression in glioma cells; HLF-mediated miR-132 directly targets and suppresses TTK kinase expression; TTK overexpression reverses the inhibitory effects of miR-132 or HLF on cancer cell proliferation, metastasis, and radioresistance, establishing an HLF→miR-132→TTK axis. Luciferase reporter assay (miR-132 promoter with BS1 site), lentiviral transduction, wound healing, transwell invasion, clonogenic assay, TTK rescue experiments Biomedicine & pharmacotherapy Medium 27522003
2017 HLF expression is confined to activated hepatic stellate cells (HSCs) in fibrotic liver; HLF transcriptionally enhances IL-6 expression and intensifies STAT3 phosphorylation to promote HSC activation; conversely, IL-6/STAT3 signaling activates HLF expression, completing a feedforward regulatory circuit; HLF loss impairs primary HSC activation and attenuates liver fibrosis in HLF-knockout mice. HLF knockout (HLF-PB/PB) mouse model, primary murine HSC isolation and culture, LX2 human HSC line, ectopic HLF expression, IL-6 and p-STAT3 measurement, patient fibrotic liver correlation Gut High 28754776
2019 HLF is an oncofetal protein reactivated in HCC by SOX2 and OCT4; HLF transcriptionally activates c-Jun to promote tumor initiating cell (TIC) generation and TIC-like properties in hepatoma cells; the HLF/c-Jun axis determines sorafenib response, and HLF interference abrogates c-Jun activation and enhances sorafenib sensitivity in patient-derived xenografts. ChIP/reporter assays for HLF→c-Jun transactivation, in vivo tumor models, patient cohort analysis, PDX sorafenib response Gut High 31118247
2019 TCF3-HLF recruits HLF binding sites at hematopoietic stem cell/myeloid lineage-associated super-enhancers to drive lineage identity and self-renewal; TCF3-HLF directly activates MYC through hijacking an HLF binding site in a MYC enhancer cluster; TCF3-HLF pioneers cooperation with ERG and recruits histone acetyltransferase EP300, conferring susceptibility to EP300 inhibition. ChIP-seq of endogenous TCF3-HLF, functional genomics, CRISPRi, EP300 inhibitor treatment, in vivo leukemia propagation assays Cancer cell High 31735627
2019 Eya2 is a direct transcriptional target of E2A-HLF, identified by ChIP-qPCR and reporter assay showing E2A-HLF binds the Eya2 promoter consensus sequence; Eya2 is highly expressed in E2A-HLF-immortalized mouse HSPCs; Eya2 knockdown in E2A-HLF-immortalized cells reduces colony-forming efficiency, demonstrating Eya2 is required for E2A-HLF-mediated self-renewal. ChIP-qPCR, luciferase reporter assay, shRNA knockdown, colony formation assay International journal of oncology Medium 30628662
2019 Hlf expression specifically marks a developmental continuum from HSC precursors to HSCs but not erythro-myeloid progenitors; in the Hlf-tdTomato reporter mouse, Hlf is expressed in intra-aortic hematopoietic clusters and fetal liver HSCs but not in EMPs; HSC specification is regulated by an Evi-1/Hlf axis, active only within Hlf+ nascent hematopoietic clusters. Hlf-tdTomato knock-in reporter mouse, in vitro co-culture, long-term transplantation assay, Evi-1/Hlf axis characterization The Journal of experimental medicine High 31076455
2020 HLF downregulation promotes NSCLC metastasis by activating NF-κB/p65 signaling through disrupting nuclear translocation of PPARα and PPARγ, thereby promoting anaerobic metabolism to support anchorage-independent growth under low nutritional conditions; both genetic deletion and methylation contribute to HLF downregulation in NSCLC. In vivo lung colonization/metastasis models, HLF overexpression/silencing, NF-κB/PPAR localization assays, metabolic assays Cancer letters Medium 32289442
2020 miR-98 suppresses hepatic stellate cell activation by directly targeting the 3'UTR of HLF mRNA (confirmed by luciferase reporter assay); HLF overexpression increases HSC activation by inducing HIF-1α expression and activating TGF-β/Smad2/3 signaling; in vivo ago-miR-98 injection attenuates liver fibrosis in multiple murine models and suppresses HLF expression. Luciferase 3'UTR reporter assay, HLF overexpression, HIF-1α induction, TGF-β/Smad2/3 pathway analysis, in vivo fibrosis models Frontiers in cell and developmental biology Medium 32637414
2021 HLF is one of the most specific transcriptional markers of human HSCs; HLF-expressing cells comprise all stem cell activity in culture and during serial transplantation; a genomic HLF reporter strategy selectively labels the most immature blood cells and tracks all hematopoietic stem cell activity, establishing HLF as a defining transcription factor of the human HSC state. Single-cell and population transcriptomics, genomic HLF reporter (knock-in), serial transplantation assay in vivo Blood High 34499717
2021 Hlf-labeled early cells (marked by Hlf-CreER at E9.5) contribute to and retain the HSC pool in adult bone marrow with long-term balanced multilineage hematopoiesis; CD45+ pre-HSCs at E10.5 exist exclusively in the Hlf-tdTomato-positive population, indicating Hlf expression is gained prior to or concurrently with CD45 during HSC specification. Hlf-tdTomato knock-in reporter, Hlf-CreER lineage tracing (single-dose induction at E9.5), long-term transplantation Frontiers in cell and developmental biology High 34589491
2022 HLF is regulated by TGF-β1 secreted by tumor-associated macrophages; HLF transactivates GGT1 (gamma-glutamyltransferase 1) to promote ferroptosis resistance, driving TNBC cell proliferation, metastasis, and cisplatin resistance; reciprocally, IL-6 from TNBC cells activates JAK2/STAT3 in macrophages to induce TGF-β1 secretion, constituting a feed-forward IL-6–TGF-β1 circuit sustaining HLF activation. ChIP/reporter assays for HLF→GGT1 transactivation, ferroptosis assays, TNBC xenograft models, cytokine pathway inhibition Journal of hematology & oncology High 34991659
2022 CircCHD2 functions as a miR-200b-3p sponge, thereby relieving miR-200b-3p-mediated repression of HLF in hepatic stellate cells; enforced HLF expression reverses the suppressive effects of miR-200b-3p overexpression on HSC proliferation and activation markers (α-SMA, Col1A1), placing HLF downstream of the circCHD2/miR-200b-3p axis in liver cirrhosis progression. Luciferase reporter assay (circCHD2/miR-200b-3p/HLF interactions), TGF-β1-stimulated LX-2 cell model, siRNA knockdown, qPCR/Western blot Journal of environmental pathology, toxicology and oncology Medium 36374958
2023 HLF activation in intrahepatic cholangiocarcinoma (ICC) is mediated by METTL3-dependent m6A methylation of HLF mRNA; HLF transcriptionally activates FZD4 and FOXQ1; FOXQ1 in turn transcriptionally activates METTL3, forming a positive feedback loop that activates WNT/β-catenin signaling and tumor stemness. RNA-seq, CUT&Tag (HLF chromatin binding), m6A methylation assay, loss/gain-of-function experiments, METTL3/HLF reporter circuit validation Cancer letters High 36958694
2023 miR-103-3p targets HLF mRNA (validated by luciferase reporter assay); miR-103-3p overexpression promotes apoptosis and inhibits autophagy in HL-1 cardiomyocytes; HLF overexpression reverses this phenotype, inhibiting apoptosis and promoting autophagy, establishing an miR-103-3p/HLF axis regulating cardiomyocyte survival. Luciferase reporter assay, HL-1 cell transfection, apoptosis assay, autophagy measurement ESC heart failure Medium 37562973
2023 HLF transcriptionally activates YAP1 expression in ovarian cancer cells; miR-520e directly targets the HLF 3'UTR (validated by reporter assay); the miR-520e/HLF/YAP1 axis modulates Hippo signaling to regulate ovarian cancer stemness, proliferation, metastasis, and carboplatin resistance. miR-520e 3'UTR reporter assay, HLF loss/gain-of-function, YAP1 reporter/expression analysis, PDX carboplatin response Cell death & disease Medium 37709768
2024 HLF expression is epigenetically silenced in metastatic ccRCC by the SWI/SNF ATPase subunit BRG1; HLF suppresses lung metastasis by regulating LPXN (leupaxin) expression, which modulates integration of collagen mechanical cues with the actin cytoskeleton through Paxillin; BRG1 inhibition restores HLF expression and reduces cell invasion across multiple cancer types. In vivo CRISPR-Cas9 genome-wide screen, HLF overexpression/depletion in ccRCC migration/metastasis assays, BRG1 ChIP/epigenetic silencing analysis, LPXN/Paxillin pathway characterization Nature communications High 40473600
2024 HLF efficiently marks HSC-fated artery endothelial cells during a narrow developmental window; guided by arterial HSC origins, hPSC differentiation through artery endothelium rapidly generates >90% pure HLF+HOXA+ hematopoietic progenitors within 10 days that express hallmark HSC transcription factors and generate multiple blood lineages. Non-invasive genetic lineage tracing in mouse embryos, hPSC stepwise differentiation protocol with defined media, single-cell profiling, in vitro multilineage differentiation Developmental cell High 38569552
2025 HLF transcriptionally activates TFEB and IL-6R as direct target genes in gallbladder cancer stem cells; the IL-6/IL-6R/STAT3 axis transactivates HLF forming a positive feedback loop; HLF promotes cancer stem cell expansion and gemcitabine resistance via TFEB-induced autophagy; HLF also drives TFEB-induced PD-L1 expression to govern CD8+ T cell-dependent immune evasion. ChIP/CUT&Tag for HLF→TFEB/IL-6R binding, luciferase reporter assays, in vivo xenograft/PDX models, CD8+ T cell depletion experiments Science advances High 40779629
2025 Bmi1 represses HLF by directly binding to its promoter (validated by luciferase reporter assay) in intrahepatic cholangiocarcinoma; HLF overexpression inhibits ICC growth in vitro and in vivo; HLF repression reverses the inhibitory effects of Bmi1 knockdown on cell survival and proliferation, establishing HLF as a tumor suppressor downstream of Bmi1 in ICC. RNA-seq, luciferase reporter assay (Bmi1 binding to HLF promoter), lentiviral overexpression/knockout, xenograft and primary ICC mouse models British journal of cancer Medium 41136715
2025 HLF transcriptionally activates SLC7A11 to inhibit trophoblast ferroptosis; WTAP-dependent m6A methylation stabilizes HLF mRNA; WTAP downregulation in preeclampsia reduces HLF levels, leading to reduced SLC7A11 expression and increased ferroptosis in trophoblasts, impairing their proliferation, migration, and invasion. Reporter assays for HLF→SLC7A11 transactivation, m6A methylation analysis, WTAP knockdown, ferroptosis assays, trophoblast functional assays FASEB journal Medium 40827901
2025 HLF and hTERT co-overexpression in human HSPCs enables partial immortalization (up to 70 days in culture) with limited differentiation capacity; HLF alone (as a stem cell maintenance regulator) is insufficient without hTERT-mediated telomere maintenance, and the combination maintains HSPC identity markers. Lentiviral co-overexpression, BaEV-mediated transduction, long-term culture, lineage differentiation assays Frontiers in bioengineering and biotechnology Medium 41602466

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 4200 10353251
2001 HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science (New York, N.Y.) 3938 11292862
2010 Hypoxia-inducible factors and the response to hypoxic stress. Molecular cell 1898 20965423
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2000 Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel-Lindau protein. Nature cell biology 1295 10878807
2002 Asparagine hydroxylation of the HIF transactivation domain a hypoxic switch. Science (New York, N.Y.) 1247 11823643
2009 A census of human transcription factors: function, expression and evolution. Nature reviews. Genetics 1191 19274049
2010 Sequencing of 50 human exomes reveals adaptation to high altitude. Science (New York, N.Y.) 1179 20595611
2003 Differential roles of hypoxia-inducible factor 1alpha (HIF-1alpha) and HIF-2alpha in hypoxic gene regulation. Molecular and cellular biology 1167 14645546
1997 Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells. Genes & development 1082 9000051
2009 Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells. Cancer cell 1071 19477429
2004 Differential function of the prolyl hydroxylases PHD1, PHD2, and PHD3 in the regulation of hypoxia-inducible factor. The Journal of biological chemistry 901 15247232
2000 Hypoxia inducible factor-alpha binding and ubiquitylation by the von Hippel-Lindau tumor suppressor protein. The Journal of biological chemistry 891 10823831
2016 Hypoxia induces the breast cancer stem cell phenotype by HIF-dependent and ALKBH5-mediated m⁶A-demethylation of NANOG mRNA. Proceedings of the National Academy of Sciences of the United States of America 889 27001847
2020 A reference map of the human binary protein interactome. Nature 849 32296183
1997 A novel bHLH-PAS factor with close sequence similarity to hypoxia-inducible factor 1alpha regulates the VEGF expression and is potentially involved in lung and vascular development. Proceedings of the National Academy of Sciences of the United States of America 847 9113979
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2005 Contrasting properties of hypoxia-inducible factor 1 (HIF-1) and HIF-2 in von Hippel-Lindau-associated renal cell carcinoma. Molecular and cellular biology 803 15964822
2008 Global analysis of host-pathogen interactions that regulate early-stage HIV-1 replication. Cell 787 18854154
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2019 A GPX4-dependent cancer cell state underlies the clear-cell morphology and confers sensitivity to ferroptosis. Nature communications 732 30962421
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
1998 The basic-helix-loop-helix-PAS orphan MOP3 forms transcriptionally active complexes with circadian and hypoxia factors. Proceedings of the National Academy of Sciences of the United States of America 656 9576906
2007 HIF-2alpha promotes hypoxic cell proliferation by enhancing c-myc transcriptional activity. Cancer cell 645 17418410
2010 Natural selection on EPAS1 (HIF2alpha) associated with low hemoglobin concentration in Tibetan highlanders. Proceedings of the National Academy of Sciences of the United States of America 619 20534544
2006 Recruitment of HIF-1alpha and HIF-2alpha to common target genes is differentially regulated in neuroblastoma: HIF-2alpha promotes an aggressive phenotype. Cancer cell 611 17097563
2010 An atlas of combinatorial transcriptional regulation in mouse and man. Cell 573 20211142
2003 Inhibition of HIF2alpha is sufficient to suppress pVHL-defective tumor growth. PLoS biology 515 14691554
1999 Molecular mechanisms of transcription activation by HLF and HIF1alpha in response to hypoxia: their stabilization and redox signal-induced interaction with CBP/p300. The EMBO journal 491 10202154
2009 Genome-wide association of hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha DNA binding with expression profiling of hypoxia-inducible transcripts. The Journal of biological chemistry 481 19386601
2014 Fructose-1,6-bisphosphatase opposes renal carcinoma progression. Nature 450 25043030
2006 The circadian PAR-domain basic leucine zipper transcription factors DBP, TEF, and HLF modulate basal and inducible xenobiotic detoxification. Cell metabolism 400 16814730
1992 Fusion of the leucine zipper gene HLF to the E2A gene in human acute B-lineage leukemia. Science (New York, N.Y.) 271 1386162
2022 HLF regulates ferroptosis, development and chemoresistance of triple-negative breast cancer by activating tumor cell-macrophage crosstalk. Journal of hematology & oncology 215 34991659
1992 Hlf, a novel hepatic bZIP protein, shows altered DNA-binding properties following fusion to E2A in t(17;19) acute lymphoblastic leukemia. Genes & development 214 1516826
2015 Genomics and drug profiling of fatal TCF3-HLF-positive acute lymphoblastic leukemia identifies recurrent mutation patterns and therapeutic options. Nature genetics 196 26214592
2003 HLF/HIF-2alpha is a key factor in retinopathy of prematurity in association with erythropoietin. The EMBO journal 194 12606578
2017 The HLF/IL-6/STAT3 feedforward circuit drives hepatic stellate cell activation to promote liver fibrosis. Gut 188 28754776
1999 SLUG, a ces-1-related zinc finger transcription factor gene with antiapoptotic activity, is a downstream target of the E2A-HLF oncoprotein. Molecular cell 171 10518215
1996 Reversal of apoptosis by the leukaemia-associated E2A-HLF chimaeric transcription factor. Nature 118 8700228
1998 Transcriptionally active heterodimer formation of an Arnt-like PAS protein, Arnt3, with HIF-1a, HLF, and clock. Biochemical and biophysical research communications 117 9704006
2019 Oncofetal HLF transactivates c-Jun to promote hepatocellular carcinoma development and sorafenib resistance. Gut 109 31118247
1995 The rat hepatic leukemia factor (HLF) gene encodes two transcriptional activators with distinct circadian rhythms, tissue distributions and target preferences. The EMBO journal 92 7556072
2006 Hypercalcemia in childhood acute lymphoblastic leukemia: frequent implication of parathyroid hormone-related peptide and E2A-HLF from translocation 17;19. Leukemia 84 17183364
2020 Downregulation of the circadian rhythm regulator HLF promotes multiple-organ distant metastases in non-small cell lung cancer through PPAR/NF-κb signaling. Cancer letters 74 32289442
2021 HLF expression defines the human hematopoietic stem cell state. Blood 68 34499717
2019 Hlf marks the developmental pathway for hematopoietic stem cells but not for erythro-myeloid progenitors. The Journal of experimental medicine 68 31076455
2010 Cardiac hypertrophy, low blood pressure, and low aldosterone levels in mice devoid of the three circadian PAR bZip transcription factors DBP, HLF, and TEF. American journal of physiology. Regulatory, integrative and comparative physiology 56 20686175
2006 Functional role of DMT1 in transferrin-independent iron uptake by human hepatocyte and hepatocellular carcinoma cell, HLF. Hepatology research : the official journal of the Japan Society of Hepatology 55 16707273
2016 HLF/miR-132/TTK axis regulates cell proliferation, metastasis and radiosensitivity of glioma cells. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 54 27522003
1994 DNA-binding and transcriptional regulatory properties of hepatic leukemia factor (HLF) and the t(17;19) acute lymphoblastic leukemia chimera E2A-HLF. Molecular and cellular biology 54 8065331
2000 Identification of multiple transcription factors, HLF, FTF, and E4BP4, controlling hepatitis B virus enhancer II. Journal of virology 49 10627534
2019 The Leukemogenic TCF3-HLF Complex Rewires Enhancers Driving Cellular Identity and Self-Renewal Conferring EP300 Vulnerability. Cancer cell 45 31735627
1999 Two candidate downstream target genes for E2A-HLF. Blood 44 9864177
1995 E2A-HLF-mediated cell transformation requires both the trans-activation domains of E2A and the leucine zipper dimerization domain of HLF. Molecular and cellular biology 44 7760820
1994 Two types of genomic rearrangements create alternative E2A-HLF fusion proteins in t(17;19)-ALL. Blood 44 8180393
1997 Cardiac expressions of HIF-1 alpha and HLF/EPAS, two basic loop helix/PAS domain transcription factors involved in adaptative responses to hypoxic stresses. Biochemical and biophysical research communications 42 9398602
2010 Identification of Zfp521/ZNF521 as a cooperative gene for E2A-HLF to develop acute B-lineage leukemia. Oncogene 38 20062079
2001 The E2A-HLF oncoprotein activates Groucho-related genes and suppresses Runx1. Molecular and cellular biology 38 11486032
1998 The chimeric E2A-HLF transcription factor abrogates p53-induced apoptosis in myeloid leukemia cells. Blood 37 9694729
2015 Hlf is a genetic modifier of epilepsy caused by voltage-gated sodium channel mutations. Epilepsy research 35 26656780
2001 CREB is one component of the binding complex of the Ces-2/E2A-HLF binding element and is an integral part of the interleukin-3 survival signal. Molecular and cellular biology 35 11416141
2010 Aberrant induction of LMO2 by the E2A-HLF chimeric transcription factor and its implication in leukemogenesis of B-precursor ALL with t(17;19). Blood 34 20519628
2024 Lineage-tracing hematopoietic stem cell origins in vivo to efficiently make human HLF+ HOXA+ hematopoietic progenitors from pluripotent stem cells. Developmental cell 33 38569552
2010 The E2A-HLF oncogenic fusion protein acts through Lmo2 and Bcl-2 to immortalize hematopoietic progenitors. Leukemia 33 21072044
1999 Expression of E2A-HLF chimeric protein induced T-cell apoptosis, B-cell maturation arrest, and development of acute lymphoblastic leukemia. Blood 32 10216071
1998 The AD1 and AD2 transactivation domains of E2A are essential for the antiapoptotic activity of the chimeric oncoprotein E2A-HLF. Molecular and cellular biology 32 9742120
1996 The proto-oncogene HLF and the related basic leucine zipper protein TEF display highly similar DNA-binding and transcriptional regulatory properties. Blood 32 8639829
2020 MicroRNA-98 Inhibits Hepatic Stellate Cell Activation and Attenuates Liver Fibrosis by Regulating HLF Expression. Frontiers in cell and developmental biology 31 32637414
1997 Cell transformation mediated by homodimeric E2A-HLF transcription factors. Molecular and cellular biology 30 9032268
2017 HMGB1 promotes HLF-1 proliferation and ECM production through activating HIF1-α-regulated aerobic glycolysis. Pulmonary pharmacology & therapeutics 29 28571757
1999 Disrupted differentiation and oncogenic transformation of lymphoid progenitors in E2A-HLF transgenic mice. Molecular and cellular biology 29 10330184
2015 MEIS1 regulates an HLF-oxidative stress axis in MLL-fusion gene leukemia. Blood 28 25740828
2001 E2A-HLF usurps control of evolutionarily conserved survival pathways. Oncogene 28 11607821
2016 Poly (ADP-ribose) polymerase inhibitors selectively induce cytotoxicity in TCF3-HLF-positive leukemic cells. Cancer letters 26 27894958
2005 TEF, an antiapoptotic bZIP transcription factor related to the oncogenic E2A-HLF chimera, inhibits cell growth by down-regulating expression of the common beta chain of cytokine receptors. Blood 26 15665112
2023 m6A RNA methylation-mediated upregulation of HLF promotes intrahepatic cholangiocarcinoma progression by regulating the FZD4/β-catenin signaling pathway. Cancer letters 24 36958694
2018 The antimicrobial cathelicidin peptide hlF(1-11) attenuates alveolar macrophage pyroptosis induced by Acinetobacter baumannii in vivo. Experimental cell research 22 29409862
2002 Transformation of bone marrow B-cell progenitors by E2a-Hlf requires coexpression of Bcl-2. Molecular and cellular biology 21 12370314
2015 Effects of fucoidan on proliferation, AMP-activated protein kinase, and downstream metabolism- and cell cycle-associated molecules in poorly differentiated human hepatoma HLF cells. International journal of oncology 20 25776104
2003 Regulation of annexin II by cytokine-initiated signaling pathways and E2A-HLF oncoprotein. Blood 20 15070701
2013 Optimizing the antitumor selectivity of PVP-Hypericin re A549 cancer cells and HLF normal cells through pulsed blue light. Photodiagnosis and photodynamic therapy 19 24284116
2012 A novel TCF3-HLF fusion transcript in acute lymphoblastic leukemia with a t(17;19)(q22;p13). Cancer genetics 19 23181981
2023 HLF promotes ovarian cancer progression and chemoresistance via regulating Hippo signaling pathway. Cell death & disease 17 37709768
2012 Oncogenic fusion E2A-HLF sensitizes t(17;19)-positive acute lymphoblastic leukemia to TRAIL-mediated apoptosis by upregulating the expression of death receptors. Leukemia 17 22743623
2006 ABCB1 over-expression and drug-efflux in acute lymphoblastic leukemia cell lines with t(17;19) and E2A-HLF expression. Pediatric blood & cancer 17 16206189
2009 A mWAP-hLF hybrid gene locus gave extremely high level expression of human lactoferrin in the milk of transgenic mice. Transgenic research 16 19219636
1999 Characteristics of L-carnitine transport in cultured human hepatoma HLF cells. The Journal of pharmacy and pharmacology 16 10504033
2021 Hlf Expression Marks Early Emergence of Hematopoietic Stem Cell Precursors With Adult Repopulating Potential and Fate. Frontiers in cell and developmental biology 15 34589491
2001 The DBP transcriptional activation domain is highly homologous to that of HLF and TEF and is not responsible for the tissue type-specific transcriptional activity of DBP. Gene 15 11223263
2023 miRNA-103-3p-Hlf regulates apoptosis and autophagy by targeting hepatic leukaemia factor in heart failure. ESC heart failure 14 37562973
2022 In Vitro Antimycobacterial Activity of Human Lactoferrin-Derived Peptide, D-hLF 1-11, against Susceptible and Drug-Resistant Mycobacterium tuberculosis and Its Synergistic Effect with Rifampicin. Antibiotics (Basel, Switzerland) 14 36551443
2021 Successful Treatment of TCF3-HLF-positive Childhood B-ALL with Chimeric Antigen Receptor T-Cell Therapy. Clinical lymphoma, myeloma & leukemia 14 33640284
2006 Characterization of the t(17;19) translocation by gene-specific fluorescent in situ hybridization-based cytogenetics and detection of the E2A-HLF fusion transcript and protein in patients' cells. Haematologica 14 16531271
2021 FLT3-ITD allelic ratio and HLF expression predict FLT3 inhibitor efficacy in adult AML. Scientific reports 13 34876631
1999 Enhanced binding of HLF/DBP heterodimers represents one mechanism of PAR protein transactivation of the factor VIII and factor IX genes. DNA and cell biology 13 10073576
2021 The advantage of chimeric antigen receptor T cell therapy in pediatric acute lymphoblastic leukemia with E2A-HLF fusion gene positivity: a case series. Translational pediatrics 11 33880339
2018 NGS-based methylation profiling differentiates TCF3-HLF and TCF3-PBX1 positive B-cell acute lymphoblastic leukemia. Epigenomics 11 29334255
2009 Up-regulation of survivin by the E2A-HLF chimera is indispensable for the survival of t(17;19)-positive leukemia cells. The Journal of biological chemistry 11 19887369
1997 The chimeric oncoproteins E2A-PBX1 and E2A-HLF are concentrated within spherical nuclear domains. Oncogene 11 9366523
2025 HLF and PPARα axis regulates metabolic-associated fatty liver disease through extracellular vesicles derived from the intestinal microbiota. iMeta 10 40236774
2022 CircCHD2/miR-200b-3p/HLF Axis Promotes Liver Cirrhosis. Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer 10 36374958
2020 Genetic Analysis Identifies the Role of HLF in Renal Cell Carcinoma. Cancer genomics & proteomics 9 33099483
2004 E4BP4 expression is regulated by the t(17;19)-associated oncoprotein E2A-HLF in pro-B cells. British journal of haematology 9 15147370
2002 E2A/HLF fusion gene in an acute lymphoblastic leukemia patient with disseminated intravascular coagulation and a normal karyotype. The hematology journal : the official journal of the European Haematology Association 8 12111652
2015 Conditional Expression of E2A-HLF Induces B-Cell Precursor Death and Myeloproliferative-Like Disease in Knock-In Mice. PloS one 7 26588248
2020 Comprehensive chromosomal aberrations in a case of a patient with TCF3-HLF-positive BCP-ALL. BMC medical genomics 6 32245383
2020 Targeting the oncogenic activity of TCF3-HLF in leukemia. Molecular & cellular oncology 5 32391417
2019 The goat β‑casein/CMV chimeric promoter drives the expression of hLF in transgenic goats produced by cell transgene microinjection. International journal of molecular medicine 5 31661123
2017 The targeting effect of Hm2E8b-NCTD-liposomes on B-lineage leukaemia stem cells is associated with the HLF-SLUG axis. Journal of drug targeting 5 28627280
2024 Combinatory Use of hLF(1-11), a Synthetic Peptide Derived from Human Lactoferrin, and Fluconazole/Amphotericin B against Malassezia furfur Reveals a Synergistic/Additive Antifungal Effect. Antibiotics (Basel, Switzerland) 4 39200089
2022 Co-Expression of Runx1, Hoxa9, Hlf, and Hoxa7 Confers Multi-Lineage Potential on Hematopoietic Progenitors Derived From Pluripotent Stem Cells. Frontiers in cell and developmental biology 4 35573697
1998 Regulation of the DBP promoter by PAR proteins and in leukemic cells bearing an E2A/HLF translocation. Biochemical and biophysical research communications 4 9571207
2025 HLF transactivates TFEB to promote gallbladder cancer stem cells' self-renewal and determines tumor response to distinct therapies. Science advances 3 40779629
2019 Eya2 is critical for the E2A‑HLF‑mediated immortalization of mouse hematopoietic stem/progenitor cells. International journal of oncology 3 30628662
2025 Protocol for the generation of HLF+ HOXA+ human hematopoietic progenitor cells from pluripotent stem cells. STAR protocols 1 39864063
2025 Construction of an anaplastic thyroid cancer stratification signature to guide immune therapy selection and validation of the pivotal gene HLF through in vitro experiments. Frontiers in immunology 1 39872516
2025 SWI/SNF ATPase silenced HLF potentiates lung metastasis in solid cancers. Nature communications 1 40473600
2024 PGV-1 Causes Disarrangement of Spindle Microtubule Organization Resulting in Aberrant Mitosis in HLF and HuH6 Cells Associated with Altered MYCN Status. Advanced pharmaceutical bulletin 1 39494255
2022 T-Cell-Replete Haploidentical Hematopoietic Stem Cell Transplantation for a Patient With Tcf3-Hlf-Positive Acute Lymphoblastic Leukemia Extramedullary Relapse After Unrelated Bone Marrow Transplantation. Journal of pediatric hematology/oncology 1 36162014
2022 Peripheral Bone Relapse of Paediatric TCF3-HLF Positive Acute Lymphoblastic Leukaemia during Haematopoietic Stem Cell Transplantation: A Case Report. Children (Basel, Switzerland) 1 36553362
2016 [BLG gene knockout and hLF gene knock-in at BLG locus in goat by TALENs]. Sheng wu gong cheng xue bao = Chinese journal of biotechnology 1 27349115
2009 [Severe hypercalcemia complicated in acute lymphoblastic leukemia (ALL) with E2A-HLF fusion gene: report of two cases and literature review]. Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi 1 19954622
2006 [p38/ERK signal pathways regulating the expression of type I collagen and activity of MMP-2 in TGF-beta1-stimulated HLF-02 cells]. Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi = Chinese journal of industrial hygiene and occupational diseases 1 16600109
2003 [Establishment and characteristics of the human diploid cell strain HLF-02]. Hunan yi ke da xue xue bao = Hunan yike daxue xuebao = Bulletin of Hunan Medical University 1 15804067
2026 HLF and hTERT cooperatively enable partial immortalization of human hematopoietic stem and progenitor cells. Frontiers in bioengineering and biotechnology 0 41602466
2025 [Analysis of 8 children with TCF3:: HLF fusion gene positive acute lymphoblastic leukemia]. Zhonghua er ke za zhi = Chinese journal of pediatrics 0 40692462
2025 WTAP Dysregulation Mediates HLF-m6A Modification to Inhibit Trophoblast Ferroptosis in Preeclampsia. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 0 40827901
2025 Bmi1 represses HLF to drive the formation and development of intrahepatic cholangiocarcinoma. British journal of cancer 0 41136715
2024 Deciphering the role of HLF in idiopathic orbital inflammation: integrative analysis via bioinformatics and machine learning techniques. Scientific reports 0 39164324