Affinage

CRLF2

Cytokine receptor-like factor 2 · UniProt Q9HC73

Length
371 aa
Mass
42.0 kDa
Annotated
2026-04-28
100 papers in source corpus 23 papers cited in narrative 23 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CRLF2 encodes a type I cytokine receptor subunit that heterodimerizes with IL-7Rα to form the functional receptor for thymic stromal lymphopoietin (TSLP), transducing signals through JAK1/2–STAT5 and PI3K/mTOR pathways via intracellular box1 domain and cytoplasmic tyrosine residues (PMID:11891057, PMID:20144186, PMID:22915648). Genomic rearrangements (P2RY8-CRLF2, IGH-CRLF2) causing CRLF2 overexpression, or the gain-of-function F232C mutation promoting constitutive dimerization, cooperate with JAK2 pseudokinase domain mutations to drive cytokine-independent proliferation and B-cell precursor acute lymphoblastic leukemia, with TSLP stimulation additionally activating ERK1/2, Rap1, and CREB signaling networks (PMID:19838194, PMID:20018760, PMID:22685175, PMID:32801162). CRLF2 overexpression in B-progenitor cells impairs B-cell differentiation and upregulates E2F signaling but is insufficient for leukemic transformation without cooperating genetic events such as mutant JAK2 or HMGN1 overexpression (PMID:35306048, PMID:34857887). Ikaros (IKZF1) directly represses CRLF2 transcription through H3K9me3 enrichment at the CRLF2 promoter, and loss of this repression contributes to aberrant CRLF2 expression in leukemia (PMID:27391346).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2001 High

    Identification of CRLF2 as a novel type I cytokine receptor with characteristic structural domains established its membership in the cytokine receptor family and its pseudoautosomal chromosomal location.

    Evidence cDNA library screening, Northern blot, and FISH mapping in human tissues

    PMID:11237741 PMID:11474172

    Open questions at the time
    • Ligand identity unknown at this stage
    • No signaling pathway activation demonstrated
    • Physiological function undetermined
  2. 2002 High

    Demonstrating that CRLF2 heterodimerizes with IL-7Rα to form the functional TSLP receptor resolved the receptor composition question and linked CRLF2 to TSLP-mediated immune signaling.

    Evidence cDNA cloning, sequence analysis, and genomic structure characterization across species

    PMID:11891057

    Open questions at the time
    • Signaling mechanism downstream of receptor engagement not yet defined
    • Role of individual intracellular residues unknown
  3. 2009 High

    Discovery of P2RY8-CRLF2 and IGH-CRLF2 rearrangements causing overexpression, the F232C gain-of-function mutation causing constitutive dimerization, and cooperation with mutant JAK2 for cytokine-independent transformation established CRLF2 as a central oncogenic scaffold in B-ALL.

    Evidence Genomic deletion analysis, Ba/F3 transformation assays, JAK-STAT signaling assays, and primary B-cell progenitor transduction across multiple independent groups

    PMID:19641190 PMID:19838194 PMID:19965641 PMID:20018760

    Open questions at the time
    • Detailed intracellular signaling requirements not dissected
    • Whether CRLF2 overexpression alone is sufficient for transformation unclear
    • In vivo leukemogenesis models not yet established
  4. 2010 High

    Systematic mutagenesis established that TSLP signaling through the CRLF2/IL-7Rα complex requires at least one cytoplasmic tyrosine residue in either chain, distinguishing TSLP from IL-7 signaling which depends specifically on IL-7Rα Y449.

    Evidence Site-directed mutagenesis of all cytoplasmic tyrosines in both receptor chains with Ba/F3 proliferation readout

    PMID:20144186

    Open questions at the time
    • Identity of specific signaling molecules recruited to CRLF2 tyrosines not established
    • Role of box1/box2 motifs not yet systematically tested
  5. 2012 High

    Domain dissection revealed that CRLF2 box1 and W286 are universally required for signaling, while Y368 is selectively required for F232C-driven but not TSLP- or mutant JAK2-driven signaling, establishing distinct intracellular wiring for different oncogenic contexts; concurrently, primary patient samples demonstrated interconnected JAK/STAT and PI3K/mTOR pathway activation downstream of CRLF2.

    Evidence Systematic domain mutagenesis with global quantitative phosphoproteomics in Ba/F3 cells; phospho-flow cytometry with JAK inhibitor treatment in primary CRLF2-rearranged ALL patient samples

    PMID:22685175 PMID:22915648

    Open questions at the time
    • Structural basis for differential Y368 requirement unknown
    • Direct kinase-substrate relationships within the PI3K/mTOR branch not mapped
  6. 2016 High

    Identifying Ikaros as a direct transcriptional repressor of CRLF2 via H3K9me3 promoter enrichment provided a mechanism explaining how IKZF1 loss-of-function mutations lead to aberrant CRLF2 upregulation in leukemia.

    Evidence ChIP assay demonstrating direct Ikaros binding to CRLF2 promoter, CK2 inhibitor treatment modulating Ikaros–CRLF2 promoter interaction

    PMID:27391346

    Open questions at the time
    • Whether other transcription factors co-regulate CRLF2 promoter not addressed
    • Chromatin-level mechanism beyond H3K9me3 not explored
  7. 2018 Medium

    Single-cell proteomics revealed that CRLF2-driven signaling in primary B-ALL involves coordinated co-activation of JAK/STAT, PI3K, and CREB pathways, and that SRC/ABL inhibition disrupts this network more effectively than JAK or PI3K inhibition alone.

    Evidence CyTOF mass cytometry of 15 primary B-ALL patient samples with pharmacological perturbation

    PMID:29796158

    Open questions at the time
    • Direct physical link between CRLF2 and SRC family kinases not demonstrated
    • Whether CREB activation is direct or indirect unknown
  8. 2020 High

    Quantitative phosphoproteomics of TSLP-stimulated CRLF2-rearranged cells expanded the signaling landscape to include phosphorylation of IGF1R, FGFR1, and Rap1 pathway components, revealing broader receptor cross-talk than previously appreciated.

    Evidence SILAC-based phosphotyrosine profiling in CRLF2-rearranged cell lines stimulated with TSLP

    PMID:32801162

    Open questions at the time
    • Whether IGF1R/FGFR1 phosphorylation is a direct consequence of CRLF2 signaling or a secondary effect not resolved
    • Functional significance of Rap1 pathway activation in leukemogenesis untested
  9. 2021 High

    HMGN1 overexpression was shown to cooperate with P2RY8-CRLF2 to drive cytokine-independent transformation and enhance JAK/STAT signaling, while also promoting P2RY8::CRLF2 fusion formation itself, establishing HMGN1 as both a predisposing and cooperating factor in CRLF2-driven leukemogenesis.

    Evidence Ba/F3 transformation assay, CRISPR/Cas9 knockout xenograft model, inducible PAR deletion model with HMGN1 expression

    PMID:34857887 PMID:37483494

    Open questions at the time
    • Mechanism by which HMGN1 promotes preferential repair to form P2RY8::CRLF2 fusion not defined at the molecular level
    • Whether HMGN1-mediated chromatin changes directly alter CRLF2 locus accessibility unknown
  10. 2022 High

    A genome-wide CRISPR screen revealed that STAT5A/B and STAT3 are largely dispensable for CRLF2-rearranged ALL cell survival, while RAS pathway regulators including CRKL are critical for fitness and ruxolitinib sensitivity, reframing the signaling dependencies of CRLF2-driven leukemia.

    Evidence Genome-wide CRISPR-Cas9 dropout screen with genetic depletion and in vivo drug testing in IgH-CRLF2-rearranged ALL cells

    PMID:34587248

    Open questions at the time
    • Why STAT5 is dispensable despite being prominently phosphorylated is mechanistically unexplained
    • Whether RAS dependency generalizes to P2RY8-CRLF2 contexts not tested
  11. 2022 Medium

    CRLF2 overexpression in a Down syndrome B-progenitor model impaired B-cell differentiation and upregulated E2F signaling but was insufficient for transformation, formally demonstrating the requirement for cooperating events.

    Evidence Dp16 mouse model with CRLF2 retroviral overexpression, immunophenotyping, and gene expression profiling

    PMID:35306048

    Open questions at the time
    • Which cooperating mutations are minimally sufficient with CRLF2 overexpression for transformation not defined in this model
    • Relevance of E2F upregulation to leukemogenesis not functionally tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of the CRLF2/IL-7Rα/TSLP ternary complex, why STAT5 is dispensable despite robust phosphorylation in CRLF2-rearranged ALL, the identity of direct kinase substrates linking CRLF2 to RAS and PI3K pathway activation, and the minimal cooperating genetic events required for CRLF2-driven leukemic transformation in vivo.
  • No crystal or cryo-EM structure of the CRLF2-containing receptor complex
  • Mechanism of STAT5 dispensability in CRLF2-rearranged ALL unexplained
  • Minimal cooperating oncogenomic lesion set for CRLF2-driven transformation undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 4
Localization
GO:0005886 plasma membrane 4
Pathway
R-HSA-1643685 Disease 5 R-HSA-168256 Immune System 4
Partners
CRKLHMGN1IKZF1IL7RJAK1JAK2STAT5ASTAT5B
Complex memberships
TSLP receptor (CRLF2/IL-7Rα heterodimer)

Evidence

Reading pass · 23 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 CRLF2 (cytokine receptor-like factor 2) was cloned as a novel type I cytokine receptor with an extracellular domain containing two fibronectin type III-like domains, four conserved cysteine residues, a WSXWS box-like motif, and an intracellular domain with box 1 and box 2-like motifs, mapping to the pseudoautosomal region Xp22.3/Yp11.3. cDNA library screening, Northern blot, FISH mapping Cytogenetics and cell genetics High 11474172
2001 CRLF2 (CRL2) is preferentially expressed on dendritic cells and activated monocytes, with expression upregulated by LPS stimulation; the intracellular domain contains a membrane-proximal box 1 motif and a conserved tyrosine residue as a potential binding site for signal transducing molecules. RT-PCR, Northern blot, immunoprecipitation of FLAG-tagged CRL2 in Ba/F3 transfectants Biochemical and biophysical research communications Medium 11237741
2002 TSLPR (CRLF2) forms a heterodimeric complex with the IL-7 receptor alpha chain to constitute the functional receptor for TSLP; the WSXWX motif in the extracellular domain is conserved across rat, mouse, and human TSLPR. cDNA cloning, sequence analysis, genomic structure characterization, zooblot analysis Gene High 11891057
2009 Interstitial deletion of the pseudoautosomal region 1 creates a P2RY8-CRLF2 fusion that juxtaposes the P2RY8 promoter with the CRLF2 coding region, causing CRLF2 overexpression; co-expression of P2RY8-CRLF2 with mutant mouse Jak2 results in constitutive JAK-STAT activation and cytokine-independent growth of Ba/F3 cells overexpressing IL-7Rα. Genomic deletion analysis, Ba/F3 cell transformation assay, JAK-STAT signaling assay Nature genetics High 19838194
2009 CRLF2 overexpression driven by IGH translocation or P2RY8-CRLF2 deletion activates the JAK-STAT pathway in cell lines and transduced primary B-cell progenitors, sustaining proliferation; CRLF2 deregulation cooperates with JAK2 pseudokinase domain mutations for oncogenic transformation. Flow cytometry-based proliferation assay, JAK-STAT pathway analysis, primary B-cell progenitor transduction Blood High 19641190
2009 CRLF2 is a type I cytokine receptor subunit that can substitute for IL-3 signaling in a functional screen; a gain-of-function CRLF2 F232C mutation promotes constitutive dimerization and cytokine-independent growth; CRLF2 serves as the key scaffold for mutant JAK2 signaling in B-ALL, as all B-ALLs with mutant JAK2 overexpress CRLF2. Functional mRNA screen in IL-3-dependent cells, mutagenesis, Ba/F3 transformation assay, JAK2 phosphorylation assay Proceedings of the National Academy of Sciences of the United States of America High 20018760
2009 The CRLF2 F232C gain-of-function mutation was identified in DS-ALL; mutant CRLF2 (F232C) and mutant JAK2 (R683) cooperate to confer cytokine-independent growth to BaF3 pro-B cells. Somatic mutation sequencing, BaF3 cytokine-independent growth assay Blood High 19965641
2010 TSLP-mediated signaling through the CRLF2/IL-7Rα heterodimer requires at least one cytoplasmic tyrosine residue; unlike IL-7 signaling which requires Y449 in IL-7Rα, tyrosine residues in both CRLF2 and IL-7Rα play redundant roles in TSLP-dependent cell proliferation — mutation of all cytoplasmic tyrosines in both chains abolishes proliferation. Site-directed mutagenesis, Ba/F3 cell proliferation assay BMC immunology High 20144186
2012 CRLF2-rearranged ALL shows increased basal levels of pJAK2, pSTAT5, and pS6; TSLP stimulation of these leukemias induces robust JAK/STAT and PI3K/mTOR pathway signaling; JAK inhibition abrogates phosphorylation of both JAK/STAT and PI3K/mTOR pathway members, demonstrating interconnection between these signaling networks. Phospho-flow cytometry of primary patient samples, TSLP stimulation assays, JAK inhibitor treatment Blood High 22685175
2012 CRLF2 signaling differs depending on mutational context: CRLF2 F232C signaling uniquely requires intracellular tyrosine Y368, while TSLP-induced or mutant JAK2-driven signaling does not; all three contexts strictly require the CRLF2 box1 domain and intracellular tryptophan W286; cells with CRLF2/mutant JAK2 show reduced phosphorylation of B-cell receptor-associated kinases (Lyn, Btk, Hck, Syk) compared to TSLP-stimulated cells, suggesting these kinases are negative regulators in the mutant JAK2 context. Domain mutagenesis analysis, global quantitative phosphotyrosine profiling, Ba/F3 signaling assays Blood High 22915648
2015 TSLPR (CRLF2) is expressed on the surface of CRLF2-overexpressing B-ALL cells and can be targeted by chimeric antigen receptor T cells (TSLPR CAR T cells) with potent in vivo leukemia-eradicating activity; short TSLPR CARs (but not long CARs) mediate leukemia regression and long-term CAR T cell persistence in xenograft models. CAR T cell construction, in vitro cytotoxicity assay, in vivo xenograft models (4 models) Blood High 26041741
2015 Human TSLP (but not mouse TSLP) activates JAK/STAT5 and PI3K/AKT/mTOR downstream pathways in CRLF2-overexpressing primary leukemia cells, demonstrating species-specific ligand-receptor signaling. Cytokine stimulation assays with phospho-signaling readouts, xenograft model comparison Haematologica Medium 26611474
2016 The IKZF1-encoded protein Ikaros directly binds to the CRLF2 promoter and suppresses CRLF2 expression in leukemia cells through enrichment of H3K9me3 histone modifications; CK2 inhibitor increases Ikaros binding to the CRLF2 promoter and suppresses CRLF2 expression in an Ikaros-dependent manner. ChIP assay, CK2 inhibitor treatment, promoter binding analysis, histone modification assay Oncotarget High 27391346
2019 CRLF2 rearrangement-driven aberrant signal transduction mediates relative glucocorticoid resistance; targeted inhibition of MEK (trametinib) or Akt (MK2206), but not JAK inhibition (ruxolitinib), was sufficient to augment glucocorticoid sensitivity in CRLF2-rearranged ALL patient-derived xenografts. Patient-derived xenograft ex vivo drug sensitivity assays, targeted kinase inhibitor treatment PloS one Medium 31318944
2021 JAK-directed PROTACs that degrade JAK2 via cereblon (CRBN) potently kill CRLF2-rearranged ALL cell lines; solving the structure of ruxolitinib and baricitinib bound to the JAK2 tyrosine kinase domain enabled rational PROTAC design; dual JAK/GSPT1-degrading PROTACs were most potent, while a JAK2-specific PROTAC (SJ1008030) showed efficacy in vivo in kinase-driven xenografts resistant to type I JAK inhibitors. Crystal structure of JAK inhibitors bound to JAK2, PROTAC synthesis and optimization, cell line and xenograft efficacy testing Blood High 34110416
2021 HMGN1 overexpression in murine stem cells and Ba/F3 cells in combination with P2RY8-CRLF2 results in cytokine-independent transformation and upregulation of JAK/STAT cell signaling pathways associated with leukemic development; HMGN1 knockout in an inducible CRISPR/Cas9 xenograft model mitigated leukemic phenotypes and increased survival. CRISPR/Cas9 knockout xenograft model, Ba/F3 cytokine-independent transformation assay, in vivo leukemia burden assessment Oncogene High 34857887
2022 CRKL depletion enhances ruxolitinib sensitivity in RAS wild-type IgH-CRLF2-rearranged ALL cells; STAT5A, STAT5B, and STAT3 are largely dispensable for IgH-CRLF2-r ALL cell survival (genome-wide CRISPR screen); regulators of RAS signaling are critical for cell fitness and ruxolitinib sensitivity. Genome-wide CRISPR-Cas9 dropout screen, genetic depletion, in vitro and in vivo drug testing Blood High 34587248
2022 CRLF2 overexpression in Dp16 (Down syndrome model) B-progenitor cells results in reduced B-cell differentiation, increased less-differentiated pre-pro-B cell proportions, and upregulated E2F signaling; CRLF2 overexpression alone did not cause leukemic transformation in recipient mice, indicating cooperating events are required. Dp16 mouse model, CRLF2 retroviral overexpression, immunophenotyping, gene expression profiling, colony assay Experimental hematology Medium 35306048
2023 HMGN1 expression increases the propensity for P2RY8::CRLF2 fusion generation; using a CRISPR/Cas9 system to induce DNA breaks at the PAR region, cells expressing HMGN1 preferentially repaired with P2RY8::CRLF2 formation compared to control cells; P2RY8::CRLF2 cells expressing HMGN1 exhibited increased proliferation, TSLPR expression, and JAK/STAT signaling. Inducible CRISPR/Cas9 modeling of PAR deletion, HMGN1 overexpression, proliferation assays, signaling pathway analysis Frontiers in oncology Medium 37483494
2020 TSLP stimulation of CRLF2-rearranged Ph-like ALL cells increases phosphorylation of JAK1, JAK2, STAT5, ERK1/2, as well as IGF1R and FGFR1; TSLP signaling is also associated with activation of the Rap1 signaling pathway in CRLF2-rearranged Ph-like ALL. Phosphotyrosine (P-Tyr) profiling with SILAC mass spectrometry in CRLF2r cell lines stimulated with TSLP Molecular cancer research : MCR High 32801162
2018 CRLF2-driven signaling in B-ALL involves co-activation of JAK/STAT, PI3K, and CREB pathways; SRC/ABL inhibition more effectively disrupts this coordinated signaling network than single-agent JAK or PI3K inhibition, including in primary minimal residual disease cells. Single-cell mass cytometry (CyTOF) of 15 primary B-ALL patient samples, pharmacological inhibitor treatment Oncotarget Medium 29796158
2023 BCL6 expression is upregulated upon JAK1/2 inhibition (ruxolitinib) in CRLF2-rearranged ALL cells; elevated BCL6 suppresses TP53 and downstream pro-apoptotic molecules (FAS, TNFRSF10B, BID, BAX, BAK, PUMA, NOXA), conferring resistance to therapy; BCL6 inhibition restores TP53 expression and augments apoptosis sensitivity. Gene expression analysis after ruxolitinib treatment, BCL6 inhibition (FX1), xenograft survival assay Haematologica Medium 36005560
2022 A novel scFv antibody fragment targeting the extracellular domain of CRLF2 (TSLPR) demonstrates receptor antagonistic effects on STAT5 signaling in CRLF2-overexpressing ALL cells, confirming that antibody binding to the CRLF2 ectodomain can block downstream JAK/STAT signaling. scFv development, CRLF2 knockdown cell line validation, STAT5 phosphorylation assay, patient-derived xenograft ex vivo association studies International journal of biological macromolecules Medium 34481852

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Rearrangement of CRLF2 in B-progenitor- and Down syndrome-associated acute lymphoblastic leukemia. Nature genetics 458 19838194
2010 Rearrangement of CRLF2 is associated with mutation of JAK kinases, alteration of IKZF1, Hispanic/Latino ethnicity, and a poor outcome in pediatric B-progenitor acute lymphoblastic leukemia. Blood 441 20139093
2009 Deregulated expression of cytokine receptor gene, CRLF2, is involved in lymphoid transformation in B-cell precursor acute lymphoblastic leukemia. Blood 375 19641190
2009 Functional screening identifies CRLF2 in precursor B-cell acute lymphoblastic leukemia. Proceedings of the National Academy of Sciences of the United States of America 270 20018760
2009 Down syndrome acute lymphoblastic leukemia, a highly heterogeneous disease in which aberrant expression of CRLF2 is associated with mutated JAK2: a report from the International BFM Study Group. Blood 265 19965641
2012 Outcome modeling with CRLF2, IKZF1, JAK, and minimal residual disease in pediatric acute lymphoblastic leukemia: a Children's Oncology Group study. Blood 195 22368272
2012 Aberrant STAT5 and PI3K/mTOR pathway signaling occurs in human CRLF2-rearranged B-precursor acute lymphoblastic leukemia. Blood 189 22685175
2018 C-Terminal End-Directed Protein Elimination by CRL2 Ubiquitin Ligases. Molecular cell 150 29775578
2010 Demographic, clinical, and outcome features of children with acute lymphoblastic leukemia and CRLF2 deregulation: results from the MRC ALL97 clinical trial. Blood 112 21106984
2015 Eradication of B-ALL using chimeric antigen receptor-expressing T cells targeting the TSLPR oncoprotein. Blood 106 26041741
2012 IGH@ translocations, CRLF2 deregulation, and microdeletions in adolescents and adults with acute lymphoblastic leukemia. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 106 22851563
2017 CRL2Lrr1 promotes unloading of the vertebrate replisome from chromatin during replication termination. Genes & development 96 28235849
2012 Outcome in children with Down's syndrome and acute lymphoblastic leukemia: role of IKZF1 deletions and CRLF2 aberrations. Leukemia 86 22441210
2018 Recognition of the Diglycine C-End Degron by CRL2KLHDC2 Ubiquitin Ligase. Molecular cell 84 30526872
2011 Function and mechanisms of TSLP/TSLPR complex in asthma and COPD. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 72 22168549
2011 A soluble thymic stromal lymphopoietin (TSLP) antagonist, TSLPR-immunoglobulin, reduces the severity of allergic disease by regulating pulmonary dendritic cells. Clinical and experimental immunology 67 21352203
2015 SELENOPROTEINS. CRL2 aids elimination of truncated selenoproteins produced by failed UGA/Sec decoding. Science (New York, N.Y.) 62 26138980
2021 Degradation of Janus kinases in CRLF2-rearranged acute lymphoblastic leukemia. Blood 60 34110416
2012 IL-3 and TNFα increase Thymic Stromal Lymphopoietin Receptor (TSLPR) expression on eosinophils and enhance TSLP-stimulated degranulation. Clinical and molecular allergy : CMA 56 22838633
2012 Small sizes and indolent evolutionary dynamics challenge the potential role of P2RY8-CRLF2-harboring clones as main relapse-driving force in childhood ALL. Blood 54 23091296
2001 Molecular cloning of a human novel type I cytokine receptor related to delta1/TSLPR. Cytogenetics and cell genetics 54 11474172
2010 CRLF2 and JAK2 in B-progenitor acute lymphoblastic leukemia: a novel association in oncogenesis. Cancer research 52 20807819
2010 CRL2(LRR-1) targets a CDK inhibitor for cell cycle control in C. elegans and actin-based motility regulation in human cells. Developmental cell 52 21074724
2017 Characterisation of the genomic landscape of CRLF2-rearranged acute lymphoblastic leukemia. Genes, chromosomes & cancer 51 28033648
2017 CRLF2-Positive B-Cell Acute Lymphoblastic Leukemia in Adult Patients: A Single-Institution Experience. American journal of clinical pathology 47 28340183
2016 Genomic and transcriptional landscape of P2RY8-CRLF2-positive childhood acute lymphoblastic leukemia. Leukemia 46 27899802
2018 Inhibition of mTORC1/C2 signaling improves anti-leukemia efficacy of JAK/STAT blockade in CRLF2 rearranged and/or JAK driven Philadelphia chromosome-like acute B-cell lymphoblastic leukemia. Oncotarget 44 29487712
2015 CRLF2 overexpression identifies an unfavourable subgroup of adult B-cell precursor acute lymphoblastic leukemia lacking recurrent genetic abnormalities. Leukemia research 43 26754556
2012 Differences in signaling through the B-cell leukemia oncoprotein CRLF2 in response to TSLP and through mutant JAK2. Blood 40 22915648
2016 High CRLF2 expression associates with IKZF1 dysfunction in adult acute lymphoblastic leukemia without CRLF2 rearrangement. Oncotarget 36 27391346
2021 Molecular basis for recognition of Gly/N-degrons by CRL2ZYG11B and CRL2ZER1. Molecular cell 35 34214466
2017 The histone deacetylase inhibitor givinostat (ITF2357) exhibits potent anti-tumor activity against CRLF2-rearranged BCP-ALL. Leukemia 35 28331226
2013 CRL2(LRR-1) E3-ligase regulates proliferation and progression through meiosis in the Caenorhabditis elegans germline. PLoS genetics 35 23555289
2012 Treatment outcome of CRLF2-rearranged childhood acute lymphoblastic leukaemia: a comparative analysis of the AIEOP-BFM and UK NCRI-CCLG study groups. British journal of haematology 35 22816614
2020 NRBP1-Containing CRL2/CRL4A Regulates Amyloid β Production by Targeting BRI2 and BRI3 for Degradation. Cell reports 34 32160551
2011 Understanding the biology of CRLF2-overexpressing acute lymphoblastic leukemia. Critical reviews in oncogenesis 33 22150304
2021 Molecular basis for ubiquitin ligase CRL2FEM1C-mediated recognition of C-degron. Nature chemical biology 32 33398170
2021 CRL2-KLHDC3 E3 ubiquitin ligase complex suppresses ferroptosis through promoting p14ARF degradation. Cell death and differentiation 32 34743205
2017 Lipopolysaccharide-Elicited TSLPR Expression Enriches a Functionally Discrete Subset of Human CD14+ CD1c+ Monocytes. Journal of immunology (Baltimore, Md. : 1950) 29 28341671
2014 An overall characterization of pediatric acute lymphoblastic leukemia with CRLF2 overexpression. Genes, chromosomes & cancer 27 24935070
2021 Combination efficacy of ruxolitinib with standard-of-care drugs in CRLF2-rearranged Ph-like acute lymphoblastic leukemia. Leukemia 26 33895784
2016 Atlas on substrate recognition subunits of CRL2 E3 ligases. Oncotarget 26 27107416
2001 Identification of a novel type I cytokine receptor CRL2 preferentially expressed by human dendritic cells and activated monocytes. Biochemical and biophysical research communications 26 11237741
2022 CRL2ZER1/ZYG11B recognizes small N-terminal residues for degradation. Nature communications 25 36496439
2021 Tumor-associated antigen Prame targets tumor suppressor p14/ARF for degradation as the  receptor protein of CRL2Prame complex. Cell death and differentiation 25 33504946
2015 A novel xenograft model to study the role of TSLP-induced CRLF2 signals in normal and malignant human B lymphopoiesis. Haematologica 25 26611474
2019 CRLF2 rearrangement in Ph-like acute lymphoblastic leukemia predicts relative glucocorticoid resistance that is overcome with MEK or Akt inhibition. PloS one 24 31318944
2017 Differential expression of MUC4, GPR110 and IL2RA defines two groups of CRLF2-rearranged acute lymphoblastic leukemia patients with distinct secondary lesions. Cancer letters 22 28866095
2019 Short ragweed pollen promotes M2 macrophage polarization via TSLP/TSLPR/OX40L signaling in allergic inflammation. Mucosal immunology 20 31350466
2018 Single-cell analysis identifies CRLF2 rearrangements as both early and late events in Down syndrome and non-Down syndrome acute lymphoblastic leukaemia. Leukemia 20 30487598
2021 UBXN7 cofactor of CRL3KEAP1 and CRL2VHL ubiquitin ligase complexes mediates reciprocal regulation of NRF2 and HIF-1α proteins. Biochimica et biophysica acta. Molecular cell research 19 33444648
2021 HMGN1 plays a significant role in CRLF2 driven Down Syndrome leukemia and provides a potential therapeutic target in this high-risk cohort. Oncogene 19 34857887
2015 Inflammatory cytokine TSLP stimulates platelet secretion and potentiates platelet aggregation via a TSLPR-dependent PI3K/Akt signaling pathway. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 19 25591759
2024 Mechanism of Ψ-Pro/C-degron recognition by the CRL2FEM1B ubiquitin ligase. Nature communications 18 38670995
2016 A potential link between TSLP/TSLPR/STAT5 and TLR2/MyD88/NFκB-p65 in human corneal epithelial cells for Aspergillus fumigatus tolerance. Molecular immunology 18 26874828
2023 Mechanism and evolutionary origins of alanine-tail C-degron recognition by E3 ligases Pirh2 and CRL2-KLHDC10. Cell reports 17 37676773
2023 CRL2APPBP2-mediated TSPYL2 degradation counteracts human mesenchymal stem cell senescence. Science China. Life sciences 17 38170390
2022 Genome-wide CRISPR-Cas9 screen identifies rationally designed combination therapies for CRLF2-rearranged Ph-like ALL. Blood 17 34587248
2014 Disruption of the TSLP-TSLPR-LAP signaling between epithelial and dendritic cells through hyperlipidemia contributes to regulatory T-Cell defects in atherosclerotic mice. Atherosclerosis 17 25544178
2023 Molecular basis for C-degron recognition by CRL2APPBP2 ubiquitin ligase. Proceedings of the National Academy of Sciences of the United States of America 14 37844242
2021 Hematological characteristics, cytogenetic features, and post-induction measurable residual disease in thymic stromal lymphopoietin receptor (TSLPR) overexpressed B-cell acute lymphoblastic leukemia in an Indian cohort. Annals of hematology 14 34159401
2014 TSLPR deficiency attenuates atherosclerotic lesion development associated with the inhibition of TH17 cells and the promotion of regulator T cells in ApoE-deficient mice. Journal of molecular and cellular cardiology 14 25117469
2022 CRL2KLHDC3 mediates p14ARF N-terminal ubiquitylation degradation to promote non-small cell lung carcinoma progression. Oncogene 12 35468939
2021 Quantitative analyses for effects of neddylation on CRL2VHL substrate ubiquitination and degradation. Protein science : a publication of the Protein Society 12 34459035
2023 Clinical, biological, and outcome features of P2RY8-CRLF2 and CRLF2 over-expression in pediatric B-cell precursor acute lymphoblastic leukemia according to the CCLG-ALL 2008 and 2018 protocol. European journal of haematology 11 36814093
2022 Nonylphenol exacerbates ovalbumin-induced allergic rhinitis via the TSLP-TSLPR/IL-7R pathway and JAK1/2-STAT3 signaling in a mouse model. Ecotoxicology and environmental safety 11 36029577
2018 SRC/ABL inhibition disrupts CRLF2-driven signaling to induce cell death in B-cell acute lymphoblastic leukemia. Oncotarget 11 29796158
2014 Gene alterations involving the CRLF2-JAK pathway and recurrent gene deletions in Down syndrome-associated acute lymphoblastic leukemia in Japan. Genes, chromosomes & cancer 11 25044358
2010 Site-directed mutagenesis reveals a unique requirement for tyrosine residues in IL-7Ralpha and TSLPR cytoplasmic domains in TSLP-dependent cell proliferation. BMC immunology 11 20144186
2023 BCL6 inhibition ameliorates resistance to ruxolitinib in CRLF2-rearranged acute lymphoblastic leukemia. Haematologica 10 36005560
2020 Combinatorial IL-17RB, ST2, and TSLPR Signaling in Dendritic Cells of Patients With Allergic Rhinitis. Frontiers in cell and developmental biology 10 32309281
2017 Whole-Genome Sequencing of a Family with Hereditary Pulmonary Alveolar Proteinosis Identifies a Rare Structural Variant Involving CSF2RA/CRLF2/IL3RA Gene Disruption. Scientific reports 10 28233860
2017 Virtual screening for inhibitors of the human TSLP:TSLPR interaction. Scientific reports 10 29222519
2017 TSLP/TSLPR promote angiogenesis following ischemic stroke via activation of the PI3K/AKT pathway. Molecular medicine reports 10 29257253
2017 Philadelphia Chromosome-like Mixed-Phenotype Acute Leukemia Demonstrating P2RY8-CRLF2 Fusion and JAK1 Mutation. American journal of clinical pathology 9 29140408
2025 Identification of a non-inhibitory aptameric ligand to CRL2ZYG11B E3 ligase for targeted protein degradation. Nature communications 8 40082426
2023 Gain of chromosome 21 increases the propensity for P2RY8::CRLF2 acute lymphoblastic leukemia via increased HMGN1 expression. Frontiers in oncology 8 37483494
2023 Preclinical development of 1B7/CD3, a novel anti-TSLPR bispecific antibody that targets CRLF2-rearranged Ph-like B-ALL. Leukemia 8 37634013
2022 High occurrence of CRLF2 abnormalities in Mexican children with B-cell acute lymphoblastic leukemia. Cytokine 8 35537330
2019 GATA3 germline variant is associated with CRLF2 expression and predicts outcome in pediatric B-cell precursor acute lymphoblastic leukemia. Genes, chromosomes & cancer 8 30859636
2023 TSLP/TSLPR promotes renal fibrosis by activating STAT3 in renal fibroblasts. International immunopharmacology 7 37364323
2022 CRLF2 overexpression defines an immature-like subgroup which is rescued through restoration of the PRC2 function in T-cell precursor acute lymphoblastic leukemia. Genes, chromosomes & cancer 7 35253299
2013 Anti-CRLF2 Antibody-Armored Biodegradable Nanoparticles for Childhood B-ALL. Particle & particle systems characterization : measurement and description of particle properties and behavior in powders and other disperse systems 7 23976822
2002 Cloning of rat thymic stromal lymphopoietin receptor (TSLPR) and characterization of genomic structure of murine Tslpr gene. Gene 7 11891057
2024 Comprehensive detection of CRLF2 alterations in acute lymphoblastic leukemia: a rapid and accurate novel approach. Frontiers in molecular biosciences 6 38370004
2022 CRLF2 overexpression results in reduced B-cell differentiation and upregulated E2F signaling in the Dp16 mouse model of Down syndrome. Experimental hematology 6 35306048
2021 CRLF2 and IKZF1 abnormalities in Mexican children with acute lymphoblastic leukemia and recurrent gene fusions: exploring surrogate markers of signaling pathways. The journal of pathology. Clinical research 6 33890726
2018 Precision medicine approaches may be the future for CRLF2 rearranged Down Syndrome Acute Lymphoblastic Leukaemia patients. Cancer letters 6 29879498
2010 Identifying the polymorphisms in the thymic stromal lymphopoietin receptor (TSLPR) and their association with asthma. BMB reports 6 20663412
2024 Co-targeting of the thymic stromal lymphopoietin receptor to decrease immunotherapeutic resistance in CRLF2-rearranged Ph-like and Down syndrome acute lymphoblastic leukemia. Leukemia 5 39681640
2022 TSLP as a Potential Therapy in the Treatment of CRLF2 B Cell Acute Lymphoblastic Leukemia. International journal of molecular sciences 5 36613920
2024 CRL2KLHDC3 and CRL1Fbxw7 cooperatively mediate c-Myc degradation. Oncogene 4 38698266
2023 An intrinsic network of polar interactions is responsible for binding of UL49.5 C-degron by the CRL2KLHDC3 ubiquitin ligase. Proteins 4 38069558
2022 Metal Allergy Mediates the Development of Oral Lichen Planus via TSLP-TSLPR Signaling. Journal of clinical medicine 4 35159975
2021 Characterization of CRLF2 Expression in Pediatric B-Cell Precursor Acute Lymphoblastic Leukemia. Clinical laboratory 4 33491417
2021 A recombinant antibody fragment directed to the thymic stromal lymphopoietin receptor (CRLF2) efficiently targets pediatric Philadelphia chromosome-like acute lymphoblastic leukemia. International journal of biological macromolecules 4 34481852
2020 Targeting TSLP-Induced Tyrosine Kinase Signaling Pathways in CRLF2-Rearranged Ph-like ALL. Molecular cancer research : MCR 4 32801162
2019 CRLF2 expression associates with ICN1 stabilization in T-cell acute lymphoblastic leukemia. Genes, chromosomes & cancer 4 30578688
2024 Synergistic drug interactions of the histone deacetylase inhibitor givinostat (ITF2357) in CRLF2-rearranged pediatric B-cell precursor acute lymphoblastic leukemia identified by high-throughput drug screening. Heliyon 3 39071567
2024 CRLF2-rearranged B-cell ALL with extramedullary lineage switch to AML following CD19-targeted therapy. Journal for immunotherapy of cancer 3 39461880