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BIOMARKER:

CRLF2 overexpression

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Other names: CRLF2, Cytokine Receptor Like Factor 2, Thymic Stromal Lymphopoietin Protein Receptor, Cytokine Receptor-Like Factor 2, TSLP Receptor, IL-XR, TSLPR, CRL2, Thymic Stromal-Derived Lymphopoietin Receptor, Cytokine Receptor CRL2 Precusor, Cytokine Receptor-Like 2, CRLF2Y, ILXR
Entrez ID:
Related biomarkers:
1m
Comprehensive detection of CRLF2 alterations in acute lymphoblastic leukemia: a rapid and accurate novel approach. (PubMed, Front Mol Biosci)
High Resolution Melting analysis unveiled concurrent CRLF2 or JAK2 variants in 8.19% of samples, as well as a dynamic nature of CRLF2 alterations during disease progression. Overall, this approach provides an accurate identification of CRLF2 alterations, enabling improved diagnostic and facilitating therapeutic decision-making.
Journal
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JAK2 (Janus kinase 2) • CRLF2 (Cytokine Receptor Like Factor 2) • IKZF1 (IKAROS Family Zinc Finger 1) • P2RY8 (P2Y Receptor Family Member 8)
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IKZF1 deletion • CRLF2 overexpression
4ms
Poor outcome of pediatric B-cell acute lymphoblastic leukemia associated with high level of CRLF2 gene expression in distinct molecular subtypes. (PubMed, Front Oncol)
Such heterogeneity was attributed to the different molecular mechanisms leading to CLRF2 upregulation, where the CRLF2 overexpression level was high in Ph-like B-ALL and medium in high hyperdiploid B-ALL. This study highlights the importance of the molecular mechanisms of the upregulation of CRLF2 expression in predicting the prognosis of pediatric B-ALL patients.
Journal
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CRLF2 (Cytokine Receptor Like Factor 2)
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CRLF2 overexpression
5ms
Updated Results from a Phase II Study of Hyper-CVAD, with or without Inotuzumab Ozogamicin, and Sequential Blinatumomab in Patients with Newly Diagnosed B-Cell Acute Lymphoblastic Leukemia (ASH 2023)
Pts received hyper-CVAD alternating with high-dose methotrexate (MTX) and cytarabine (Ara-C) for up to 4 cycles, followed by 4 cycles of blinatumomab at standard doses. Pts with CD20+ disease (≥1% cells) received 8 doses of ofatumumab (2000 mg) or rituximab (375 mg/m2)...One pt discontinued blinatumomab due to a related adverse event (grade 2 encephalopathy and dysphasia). No pts discontinued INO due to toxicity, and no cases of veno-occlusive disease have been observed.
Clinical • P2 data
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TP53 (Tumor protein P53) • ABL1 (ABL proto-oncogene 1) • CD20 (Membrane Spanning 4-Domains A1) • KMT2A (Lysine Methyltransferase 2A) • CRLF2 (Cytokine Receptor Like Factor 2) • NUP214 (Nucleoporin 214)
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TP53 mutation • KMT2A rearrangement • MLL rearrangement • TP53 expression • CRLF2 overexpression • NUP214-ABL1 fusion • ABL1 fusion
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Rituxan (rituximab) • cytarabine • Blincyto (blinatumomab) • Besponsa (inotuzumab ozogamicin) • Arzerra (ofatumumab) • methotrexate IV
5ms
An antibody fragment-decorated liposomal conjugate targets Philadelphia-like acute lymphoblastic leukemia. (PubMed, Int J Biol Macromol)
Cell apoptosis assays demonstrated the CRLF2-dependent potency of CRLF2-DM1 LIP in Ph-like ALL cell lines. This study is the first to highlight the therapeutic potential of a CRLF2-directed scFv-Fc-liposomal conjugate for targeting Ph-like ALL.
Journal
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CRLF2 (Cytokine Receptor Like Factor 2) • CD22 (CD22 Molecule)
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CRLF2 overexpression
5ms
Outcomes in Children, Adolescents, and Young Adults With Down Syndrome and ALL: A Report From the Children's Oncology Group. (PubMed, J Clin Oncol)
Patients with DS-ALL exhibit an increased rate of relapse and particularly of treatment-related mortality. Novel, less-toxic therapeutic strategies are needed to improve outcomes.
Journal
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CRLF2 (Cytokine Receptor Like Factor 2)
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CRLF2 overexpression
9ms
Prognostic relevance of surface expression of cytokine receptor-like factor 2 in pediatric B-lineage acute lymphoblastic leukemia. (PubMed, Am J Cancer Res)
Furthermore, concomitant CNA of IKZF1 in CRLF2 positive patients was associated with a greater hazard for poor overall and event free survival, compared to patients without these alterations or presence of any one of them. Our findings demonstrate that the surface CRLF2 expression in association with IKZF1 copy number alteration can be used to risk stratify pediatric B-ALL patients.
Journal
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JAK2 (Janus kinase 2) • CRLF2 (Cytokine Receptor Like Factor 2) • IKZF1 (IKAROS Family Zinc Finger 1) • PAX5 (Paired Box 5) • IL7R (Interleukin 7 Receptor) • P2RY8 (P2Y Receptor Family Member 8)
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JAK2 mutation • CRLF2 overexpression • CRLF2 mutation
9ms
'Evaluation of adverse prognostic gene alterations & MRD positivity in BCR::ABL1-like B-lineage acute lymphoblastic leukaemia patients, in a resource-constrained setting. (PubMed, Br J Cancer)
With this practical approach, we reported a high incidence of BCR::ABL1-like ALLs, and a lower frequency of CRLF2 alteration & associated CGFs. Recognising this entity, early at diagnosis is crucial to optimise personalised treatment strategies.
Journal • Minimal residual disease
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ABL1 (ABL proto-oncogene 1) • JAK2 (Janus kinase 2) • CRLF2 (Cytokine Receptor Like Factor 2) • IKZF1 (IKAROS Family Zinc Finger 1) • CD33 (CD33 Molecule) • ANPEP (Alanyl Aminopeptidase, Membrane)
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JAK2 mutation • CRLF2 overexpression • ABL1 deletion
9ms
Approach to Ph-Like ALL (SOHO 2023)
However, long-term efficacy remains to be determined and it is under evaluation in clinical trials.1,22,23 Preclinical and more recent clinical studies have shown variable activity of JAK inhibitors in JAK-STAT activating ALL17,24 and the need to simultaneously inhibit multiple pathways, including phosphoinositide 3-kinase (PI3K)/mTOR or mitogen-activated protein kinase (MEK)/ receptor tyrosine kinases (e.g. FLT3) to block the growth of leukemic blasts.25–27 Promising alternative approaches to TKIs are represented by antibody-based (e.g. blinatumomab or inozutumab) and cellular (CAR T-cell therapy) immunotherapy which have shown discernable efficacy in BCR::ABL1-like ALL among other subtypes.28–30 Moreover, the efficacy of proteolysis-targeting chimeras (PROTACs) directed against JAK231 or GSPT1/2 degraders32 has been recently reported in preclinical models of CRLF2-rearranged and other JAK-activated BCR::ABL1-like ALL. Conclusions BCR::ABL1-like ALL is driven by numerous targetable kinase fusions whose diagnosis requires the use of comprehensive assays. The incorporation of TKIs and/or different immunotherapies is reversing the historically poor outcome of this ALL subtype.
IO biomarker
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FLT3 (Fms-related tyrosine kinase 3) • ABL1 (ABL proto-oncogene 1) • NTRK3 (Neurotrophic tyrosine kinase, receptor, type 3) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • RB1 (RB Transcriptional Corepressor 1) • IGH (Immunoglobulin Heavy Locus) • PDGFRB (Platelet Derived Growth Factor Receptor Beta) • ETV6 (ETS Variant Transcription Factor 6) • CRLF2 (Cytokine Receptor Like Factor 2) • IKZF1 (IKAROS Family Zinc Finger 1) • CDKN2B (Cyclin Dependent Kinase Inhibitor 2B) • PAX5 (Paired Box 5) • JAK3 (Janus Kinase 3) • P2RY8 (P2Y Receptor Family Member 8) • ABL2 (ABL Proto-Oncogene 2, Non-Receptor Tyrosine Kinase) • CSF1R (Colony stimulating factor 1 receptor) • EBF1 (EBF Transcription Factor 1) • GSPT1 (G1 To S Phase Transition 1) • IL7 (Interleukin 7) • TSLP (Thymic Stromal Lymphopoietin)
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NTRK3 fusion • CDKN2A deletion • CRLF2 rearrangement • CRLF2 overexpression • CRLF2 mutation • EPOR rearrangement • JAK2 fusion
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Blincyto (blinatumomab)
10ms
Definition and Prognostic Value of Ph-like and IKZF1plus Status in Children With Down Syndrome and B-cell Precursor Acute Lymphoblastic Leukemia. (PubMed, Hemasphere)
Notably, ex vivo drug screening revealed sensitivity of IKZF1plus blasts for drugs active against Ph-like ALL such as Birinapant and histone deacetylase inhibitors. We provided data in a large setting of a rare condition (DS-ALL) supporting that these patients, not associated with other high-risk features, need tailored therapeutic strategies.
Journal
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CRLF2 (Cytokine Receptor Like Factor 2) • IKZF1 (IKAROS Family Zinc Finger 1) • PAX5 (Paired Box 5) • P2RY8 (P2Y Receptor Family Member 8)
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IKZF1 deletion • CRLF2 overexpression • IKZF1 overexpression • PAX5 fusion
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birinapant (IGM-9427)
11ms
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. (PubMed, Eur J Haematol)
These findings indicate P2RY8-CRLF2 identifies a subset of patients with specific features and adverse outcomes that could be improved by risk-directed treatment.
Journal
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RUNX1 (RUNX Family Transcription Factor 1) • ETV6 (ETS Variant Transcription Factor 6) • CRLF2 (Cytokine Receptor Like Factor 2) • CD22 (CD22 Molecule) • CD34 (CD34 molecule) • P2RY8 (P2Y Receptor Family Member 8) • CD7 (CD7 Molecule) • CEACAM6 (CEA Cell Adhesion Molecule 6) • CD86 (CD86 Molecule)
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CRLF2 overexpression • CD7 expression
1year
Genomic and proteomic characterization of Philadelphia-like B-lineage acute lymphoblastic leukemia: A report of Indian patients. (PubMed, Cancer)
In developing countries, detecting Philadelphia (Ph)-like B-lineage acute lymphoblastic leukemia is complicated and challenging due to its diverse genetic landscape. There is no well-defined and cost-effective methodology for its detection. The incidence of this high-risk subtype is very high in adult cases, and there is an urgent need for its accurate detection. We have developed an online PHi-RACE classifier for its rapid detection, followed by delineating the genomic and proteomic landscape of Ph-like acute lymphoblastic leukemias for the first time in Indian patients.
Journal
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JAK2 (Janus kinase 2) • CRLF2 (Cytokine Receptor Like Factor 2) • P2RY8 (P2Y Receptor Family Member 8) • IGKC (Immunoglobulin Kappa Constant) • NDUFA2 (NADH:Ubiquinone Oxidoreductase Subunit A2)
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CRLF2 overexpression • IGH translocation • JAK2 rearrangement
1year
New P1/2 trial
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JAK2 (Janus kinase 2) • CRLF2 (Cytokine Receptor Like Factor 2) • JAK1 (Janus Kinase 1) • IL7R (Interleukin 7 Receptor) • STAT5B (Signal Transducer And Activator Of Transcription 5B) • P2RY8 (P2Y Receptor Family Member 8) • EPOR (Erythropoietin Receptor) • PTPN2 (Protein Tyrosine Phosphatase Non-Receptor Type 2) • SH2B3 (SH2B Adaptor Protein 3) • DDX3X (DEAD-Box Helicase 3 X-Linked) • USP9X (Ubiquitin Specific Peptidase 9 X-Linked)
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CRLF2 rearrangement • CRLF2 overexpression • IL7R mutation • IGH-CRLF2 fusion • PTPN2 mutation
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Venclexta (venetoclax) • cytarabine • Jakafi (ruxolitinib) • cyclophosphamide
1year
TSLP as a Potential Therapy in the Treatment of CRLF2 B Cell Acute Lymphoblastic Leukemia. (PubMed, Int J Mol Sci)
Mechanistically, we showed that high doses of TSLP induced loss of its receptor and loss of CRLF2 signals in vitro. These results suggest that high doses of TSLP could be further investigated as a potential therapy for the treatment of CRLF2 B-ALL.
Journal
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CRLF2 (Cytokine Receptor Like Factor 2) • IL7R (Interleukin 7 Receptor) • IL7 (Interleukin 7) • TSLP (Thymic Stromal Lymphopoietin)
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CRLF2 overexpression
over1year
A CRLF2 Rearrangement in a Pediatric Patient with B-ALL Detected by FISH Within the Context of a Complex Abnormal Karyotype. (PubMed, J Assoc Genet Technol)
The presence of CRLF2 rearrangements within the context of a complex karyotype is often associated with CRLF2 overexpression and poor prognosis. The heterogeneity of B-ALL and the variability in the outcomes of patients that lack characteristic genetic abnormalities highlight the importance of profiling unusual genetic cases such as this one and continuing research to understand the molecular mechanisms of rarer mutations.
Journal
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RUNX1 (RUNX Family Transcription Factor 1) • ETV6 (ETS Variant Transcription Factor 6) • CRLF2 (Cytokine Receptor Like Factor 2)
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CRLF2 rearrangement • CRLF2 overexpression
over1year
Ph-like and IKZF1plus Features in Children with Down Syndrome and B Cell Precursor Acute Lymphoblastic Leukemia (ASH 2022)
Performing an ex-vivo drug screening with 174 drugs in early to late clinical trials on blasts of 3 IKZF1plus DS-ALL patients and on 14 controls (5 B-cell lymphoblastoid cell lines, 3 PBMCs, 3 T-cells and 3 CD34+ cells, all derived from healthy donors) we observed the efficacy of drugs known to be effective in Ph-like patients such as Birinapant, a SMAC mimetic, and HDAC inhibitors...Ph-like signature and IKZF1 deletions were associated with poor outcome, with the risk of relapse further increased for IKZF1plus patients. These alterations characterize subgroups of DS-ALL patients who need tailored therapeutic strategies.
Clinical
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ABL1 (ABL proto-oncogene 1) • NTRK3 (Neurotrophic tyrosine kinase, receptor, type 3) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • JAK2 (Janus kinase 2) • CRLF2 (Cytokine Receptor Like Factor 2) • IKZF1 (IKAROS Family Zinc Finger 1) • CDKN2B (Cyclin Dependent Kinase Inhibitor 2B) • PAX5 (Paired Box 5) • CD34 (CD34 molecule) • P2RY8 (P2Y Receptor Family Member 8)
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CDKN2A deletion • IKZF1 deletion • JAK2 mutation • CRLF2 overexpression • PAX5 overexpression • PAX5 fusion
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birinapant (IGM-9427)
over1year
Dissecting Ph-like ALL: The Role of Genomic Lesion and Minimal Residual Disease in Refining Outcome (ASH 2022)
The GIMEMA LAL2317 is a clinical trial designed for newly diagnosed adult B-lineage Ph-negative ALL that includes two cycles of blinatumomab in the consolidation phase...1. Chiaretti S et al., BJH 2018
Minimal residual disease
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ABL1 (ABL proto-oncogene 1) • JAK2 (Janus kinase 2) • CD19 (CD19 Molecule) • ETV6 (ETS Variant Transcription Factor 6) • CRLF2 (Cytokine Receptor Like Factor 2) • IKZF1 (IKAROS Family Zinc Finger 1) • PAX5 (Paired Box 5) • P2RY8 (P2Y Receptor Family Member 8)
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CD19 positive • IKZF1 deletion • CRLF2 overexpression • IKZF1 mutation • ABL1 deletion
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Blincyto (blinatumomab)
over1year
A Single-Tube NGS Assay for Simultaneous Detection of DNA and RNA Biomarkers as a Comprehensive Solution for Clinical Management and Guiding Therapeutic Intervention of Phlike ALL Patients (AMP 2022)
We demonstrate the use of a single-tube multimodal NGS assay for comprehensive genomics profiling that simultaneously screens DNA and RNA for expression and variants. It is a powerful and cost-effective tool to help classify PhL B-ALL subgroup for clinical management and guiding therapeutic intervention.
Clinical • Next-generation sequencing
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FLT3 (Fms-related tyrosine kinase 3) • ABL1 (ABL proto-oncogene 1) • CRLF2 (Cytokine Receptor Like Factor 2) • IKZF1 (IKAROS Family Zinc Finger 1) • LMNA (Lamin A/C) • P2RY8 (P2Y Receptor Family Member 8) • MAFB (MAF BZIP Transcription Factor B)
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BCR-ABL1 fusion • CRLF2 overexpression • CRLF2 mutation • IGH-CRLF2 fusion
over1year
Efficacy of ruxolitinib in acute lymphoblastic leukemia: A systematic review. (PubMed, Leuk Res)
Therapy with ruxolitinib led to complete (n = 7) and partial (n = 2) remission, in three individuals no information was found. Based on the limited number of studies describing the efficacy of ruxolitinib as an additional compound administrated with standard ALL therapy, we conclude that this approach can be considered in patients with aberrations activating JAK-STAT pathway.
Review • Journal
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ABL1 (ABL proto-oncogene 1) • BCR (BCR Activator Of RhoGEF And GTPase) • JAK2 (Janus kinase 2) • CRLF2 (Cytokine Receptor Like Factor 2) • IKZF1 (IKAROS Family Zinc Finger 1)
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BCR-ABL1 fusion • IKZF1 deletion • CRLF2 overexpression
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Jakafi (ruxolitinib)
over1year
Multiparametric flow cytometry directing the evaluation of CRLF2 rearrangements and JAK2 status in pediatric B cell precursor acute lymphoblastic leukemia. (PubMed, Hematol Transfus Cell Ther)
The identification of the CRLF2 antigen using the MFC, based on the percentage of positivity and MFI values, is a useful tool for predicting JAK2 mutations and CRLF2-r.
Journal
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JAK2 (Janus kinase 2) • CRLF2 (Cytokine Receptor Like Factor 2)
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CRLF2 rearrangement • JAK2 mutation • CRLF2 overexpression • CRLF2 mutation
over1year
OUTCOMES IN CHILDREN, ADOLESCENTS, AND YOUNG ADULTS WITH DOWN SYNDROME AND ACUTE LYMPHOBLASTIC LEUKEMIA: A REPORT FROM THE CHILDREN’S ONCOLOGY GROUP (SIOP 2022)
Mucositis, infections, and hyperglycemia were significantly more frequent in all patients with DS, while seizures were more frequent in patients with DS on HR trials (4.1% vs 1.7%, p = 0.001).ConclusionsPatients with DS B-ALL exhibit increased rates of treatment toxicity, death during treatment, and relapse. Novel therapeutic strategies are needed to improve these outcomes.
Clinical
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CRLF2 (Cytokine Receptor Like Factor 2)
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CRLF2 overexpression
almost2years
High occurrence of CRLF2 abnormalities in Mexican children with B-cell acute lymphoblastic leukemia. (PubMed, Cytokine)
In conclusion, in our cohort, a high occurrence of CRLF2 abnormalities was documented, particularly the P2RY8-CRLF2 rearrangement, which might represent a characteristic of the Mexican population. Targeted therapy to treat this group of patients could improve OS.
Journal
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CRLF2 (Cytokine Receptor Like Factor 2) • P2RY8 (P2Y Receptor Family Member 8)
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CRLF2 rearrangement • CRLF2 overexpression • IGH-CRLF2 fusion
almost2years
Genetic and Epigenetic Mechanisms Deregulate the CRL2 Complex in Hepatocellular Carcinoma. (PubMed, Front Genet)
Combining miRNA and mRNA expression, DNA copy number, and methylation status into one multidimensional survival analysis, we found a significant association between greater numbers of alterations and poorer overall survival for multiple component genes. While the intricacies of CRL2 complex gene regulation require additional research, it is evident that multiple causes for the deregulation of these genes must be considered in HCC, including non-traditional mechanisms.
Journal
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CRLF2 (Cytokine Receptor Like Factor 2) • MIR139 (MicroRNA 139)
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CRLF2 overexpression
almost2years
CRLF2 overexpression defines an immature-like subgroup which is rescued through restoration of the PRC2 function in T-cell precursor acute lymphoblastic leukaemia. (PubMed, Genes Chromosomes Cancer)
We identified that IKZF1 transcripts with intron retention were upregulated in the CRLF2-high subgroup. Here, we delineated the gene expression profile of CRLF2-high T-ALL samples and unravelled the crucial role of PRC2 in CRLF2 regulation in ETP-ALL.
Journal
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PTEN (Phosphatase and tensin homolog) • RUNX1 (RUNX Family Transcription Factor 1) • CRLF2 (Cytokine Receptor Like Factor 2) • IKZF1 (IKAROS Family Zinc Finger 1) • JAK3 (Janus Kinase 3) • PHF6 (PHD Finger Protein 6)
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PTEN mutation • RUNX1 mutation • EZH2 mutation • CRLF2 overexpression • JAK3 mutation • PHF6 mutation
almost2years
CRLF2 overexpression results in reduced B cell differentiation and upregulated E2F signaling in the Dp16 mouse model of Down syndrome. (PubMed, Exp Hematol)
Thus, CRLF2 overexpression results in reduced B cell differentiation and enhanced E2F signaling in Dp16 B-progenitor cells and DS-ALL patient samples. These findings suggest a functional basis for the high frequency of CRLF2-R in DS-ALL as well as a potential therapeutically targetable pathway.
Preclinical • Journal
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CRLF2 (Cytokine Receptor Like Factor 2)
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CRLF2 rearrangement • CRLF2 overexpression
almost2years
BIMODAL TARGETING OF CYTOKINE RECEPTOR-LIKE FACTOR 2 (CRLF2) WITH JAK INHIBITION AND CHIMERIC ANTIGEN RECEPTOR T CELL IMMUNOTHERAPY IN DOWN SYNDROME ACUTE LYMPHOBLASTIC LEUKEMIA (EHA 2022)
These genetic alterations induce constitutive JAK/STAT and other kinase signaling that may be targetable by the JAK1/2 inhibitor ruxolitinib...These results suggest potential for both anti-ALL efficacy and CRS dampening when JAK inhibition and TSLPRCART are properly time-sequenced and may have broader applicability for toxicity mitigation with other cellular immunotherapies. Studies of CAR T cell immunotherapy and other kinase inhibitors in additional CRLF2 -rearranged and non-rearranged DS-ALL models are ongoing.
CAR T-Cell Therapy • IO biomarker
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ABL1 (ABL proto-oncogene 1) • BCR (BCR Activator Of RhoGEF And GTPase) • CRLF2 (Cytokine Receptor Like Factor 2) • IL2 (Interleukin 2) • TSLP (Thymic Stromal Lymphopoietin)
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CRLF2 rearrangement • BCR-ABL1 mutation • CRLF2 overexpression
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Jakafi (ruxolitinib)