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BIOMARKER:

IL7R mutation

i
Other names: IL7R, Interleukin 7 Receptor, Interleukin-7 Receptor Subunit Alpha, IL-7 Receptor Subunit Alpha, L-7R Subunit Alpha, CD127 Antigen, IL-7R-Alpha, Interleukin 7 Receptor Isoform H5-6, Interleukin 7 Receptor Alpha Chain, CDW127, CDw127, IL-7RA, CD127, IL7RA, ILRA
Entrez ID:
Related biomarkers:
1m
Hyperactive STAT5 hijacks T cell receptor signaling and drives immature T cell acute lymphoblastic leukemia. (PubMed, J Clin Invest)
We provide genetic and biochemical proof that STAT5A and STAT5B hyperactivation can initiate T-ALL through TCR pathway hijacking and suggest similar mechanisms for other T cell cancers. Thus, STAT5 or TCR component blockade are targeted therapy options, particularly in patients with chemoresistant clones carrying STAT5BN642H.
Journal • IO biomarker
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STAT3 (Signal Transducer And Activator Of Transcription 3) • IL7R (Interleukin 7 Receptor) • STAT5B (Signal Transducer And Activator Of Transcription 5B) • STAT5A (Signal Transducer And Activator Of Transcription 5A)
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IL7R mutation • STAT5B N642H
6ms
Mechanism of co-operation of mutant IL-7Rα and mutant NRAS in acute lymphoblastic leukemia: role of MYC. (PubMed, Haematologica)
We suggest that MYC protein stability can be regulated by PLK-1 kinase, which was increased mainly by the NRAS signal. These studies identify novel pathways of oncogenesis and new targets for intervention that could lead to better therapeutic development.
Journal • IO biomarker
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NRAS (Neuroblastoma RAS viral oncogene homolog) • BCL2 (B-cell CLL/lymphoma 2) • IL7R (Interleukin 7 Receptor) • PLK1 (Polo Like Kinase 1)
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NRAS mutation • BCL2 expression • MYC expression • IL7R mutation
6ms
Ruxolitinib and Chemotherapy in Adolescents and Young Adults With Ph-like Acute Lymphoblastic Leukemia (clinicaltrials.gov)
P1, N=15, Recruiting, University of Chicago | Trial completion date: Sep 2024 --> Sep 2027 | Trial primary completion date: Sep 2023 --> Sep 2026
Trial completion date • Trial primary completion date
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JAK2 (Janus kinase 2) • CRLF2 (Cytokine Receptor Like Factor 2) • IL7R (Interleukin 7 Receptor) • SH2B3 (SH2B Adaptor Protein 3)
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CRLF2 rearrangement • JAK2 mutation • IL7R mutation • JAK2 rearrangement • SH2B3 deletion
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Rituxan (rituximab) • cytarabine • doxorubicin hydrochloride • Jakafi (ruxolitinib) • cyclophosphamide • vincristine • Oncaspar liquid (pegaspargase) • mercaptopurine • thioguanine
7ms
Dependence of IL-7R-Mediated Signaling on Sphingosine Kinase Activity in Acute Lymphoblastic Leukemia, but Not Healthy Lymphoid Cells, Is an Exploitable Therapeutic Vulnerability (ASH 2023)
Overall, our studies demonstrate that SKs are key players in oncogenic, but not in physiological, IL-7/IL-7R-mediated signaling. We uncover the importance of the SK-IL7R signaling crosstalk in ALL and pinpoint the therapeutic potential of SK inhibitors for IL-7R-dependent ALL.
Clinical
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IL7R (Interleukin 7 Receptor) • IL7 (Interleukin 7)
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IL7R mutation
1year
IL7-RECEPTOR EXPRESSION IS FREQUENT IN T-CELL ACUTE LYMPHOBLASTIC LEUKEMIA AND PREDICTS SENSITIVITY TO JAK-INHIBITION (EHA 2023)
Background: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy with a dismal prognosis related to refractory/relapsing diseases, raising the need for new targeted-therapies. Altogether, this study provides valuable information to optimize translation of JAKi and venetoclax to clinics for T-ALL patients with relapse who need therapeutics to bridge to transplant. This treatment protocol may benefit to a larger group of patients who may be selected with an easily applicable flow-cytometry-based companion test. IL7R-expression can be used as a biomarker for sensitivity to JAK-inhibition, thereby expanding the fraction of T- ALL patients eligible to JAKi up to nearly ~70% of T-ALL.
IO biomarker
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BCL2 (B-cell CLL/lymphoma 2) • IL7R (Interleukin 7 Receptor) • IL7 (Interleukin 7) • ANXA5 (Annexin A5)
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IL7R mutation • IL7R expression
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Venclexta (venetoclax) • Jakafi (ruxolitinib)
1year
Ruxolitinib and Chemotherapy in Adolescents and Young Adults With Ph-like Acute Lymphoblastic Leukemia (clinicaltrials.gov)
P1, N=15, Recruiting, University of Chicago | Trial primary completion date: Sep 2022 --> Sep 2023
Trial primary completion date • Combination therapy
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JAK2 (Janus kinase 2) • CRLF2 (Cytokine Receptor Like Factor 2) • IL7R (Interleukin 7 Receptor) • SH2B3 (SH2B Adaptor Protein 3)
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CRLF2 rearrangement • JAK2 mutation • IL7R mutation • JAK2 rearrangement • SH2B3 deletion
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Rituxan (rituximab) • cytarabine • doxorubicin hydrochloride • Jakafi (ruxolitinib) • cyclophosphamide • vincristine • Oncaspar liquid (pegaspargase) • mercaptopurine • thioguanine
1year
IL7-receptor expression is frequent in T-cell acute lymphoblastic leukemia and predicts sensitivity to JAK-inhibition. (PubMed, Blood)
Conversely, mutants were more sensitive to venetoclax than expressers. This provides proof of concept for translation of this strategy into clinics as bridge to transplant. Altogether, IL7R-expression can be used as a biomarker for sensitivity to JAK-inhibition, thereby expanding the fraction of T-ALL patients eligible to ruxolitinib up to nearly ~70% of T-ALL.
Journal
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IL7R (Interleukin 7 Receptor) • IL7 (Interleukin 7)
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IL7R mutation • IL7R expression
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Venclexta (venetoclax) • Jakafi (ruxolitinib)
1year
CD127 is expressed by acute lymphoblastic leukemias and is efficiently targeted by the IL7R-antagonist OSE-127 through macrophage-mediated antibody dependent phagocytosis (AACR 2023)
In fact, ADCP levels induced by OSE-127 treatment in vitro correlated with its capacity to reduce ALL blasts in the blood of PDX mice in vivo. Altogether, through its dual mode of action, OSE-127 may represent a powerful novel immunotherapy option for ALL patients, including cases with dysregulated IL7R signaling, particularly in combination with standard of care polychemotherapy.
IO biomarker
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ABL1 (ABL proto-oncogene 1) • BCR (BCR Activator Of RhoGEF And GTPase) • IL7R (Interleukin 7 Receptor) • PBX1 (PBX Homeobox 1) • IL7 (Interleukin 7)
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IL7R mutation • IL7R expression
|
lusvertikimab (OSE-127)
1year
New P1/2 trial
|
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
AALL1521: A Phase 2 Study of Ruxolitinib With Chemotherapy in Children With Acute Lymphoblastic Leukemia (clinicaltrials.gov)
P2, N=171, Active, not recruiting, Incyte Corporation | Recruiting --> Active, not recruiting
Enrollment closed
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JAK2 (Janus kinase 2) • CRLF2 (Cytokine Receptor Like Factor 2) • JAK1 (Janus Kinase 1) • IL7R (Interleukin 7 Receptor) • EPOR (Erythropoietin Receptor) • SH2B3 (SH2B Adaptor Protein 3)
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CRLF2 rearrangement • JAK2 mutation • IL7R mutation • JAK2 fusion • SH2B3 deletion
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cytarabine • doxorubicin hydrochloride • Jakafi (ruxolitinib) • cyclophosphamide • vincristine • prednisone • leucovorin calcium • Oncaspar liquid (pegaspargase) • mercaptopurine • thioguanine • Erwinase (erwinia L-asparaginase)
almost2years
AALL1521: A Phase 2 Study of Ruxolitinib With Chemotherapy in Children With Acute Lymphoblastic Leukemia (clinicaltrials.gov)
P2, N=170, Recruiting, Incyte Corporation | Trial completion date: Dec 2024 --> Sep 2025 | Trial primary completion date: Dec 2024 --> Sep 2025
Trial completion date • Trial primary completion date
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JAK2 (Janus kinase 2) • CRLF2 (Cytokine Receptor Like Factor 2) • JAK1 (Janus Kinase 1) • IL7R (Interleukin 7 Receptor) • EPOR (Erythropoietin Receptor) • SH2B3 (SH2B Adaptor Protein 3)
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CRLF2 rearrangement • JAK2 mutation • IL7R mutation • JAK2 fusion • SH2B3 deletion
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cytarabine • doxorubicin hydrochloride • Jakafi (ruxolitinib) • cyclophosphamide • vincristine • prednisone • leucovorin calcium • Oncaspar liquid (pegaspargase) • mercaptopurine • thioguanine • Erwinase (erwinia L-asparaginase)
almost2years
Mutant IL7R collaborates with MYC to induce T-cell acute lymphoblastic leukemia. (PubMed, Leukemia)
Moreover, limiting-dilution cell transplantation experiments reveal that activated IL-7R signaling increases the overall frequency of leukemia propagating cells. Our work highlights a synergy between mutant IL7R and Myc in inducing T-ALL and demonstrates that mutant IL7R enriches for leukemia propagating potential.
Journal
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MYC (V-myc avian myelocytomatosis viral oncogene homolog) • IL7R (Interleukin 7 Receptor) • IL7 (Interleukin 7)
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MYC expression • IL7R mutation • IL7R expression
2years
Overcoming Steroid Resistance in Pediatric Acute Lymphoblastic Leukemia-The State-of-the-Art Knowledge and Future Prospects. (PubMed, Int J Mol Sci)
A typical ALL treatment includes three phases: remission induction and consolidation and maintenance, preceded by a prednisone prephase. MAPK-ERK pathway inhibitors were demonstrated to enhance the results of dexamethasone therapy in preclinical ALL studies. This report summarizes steroids' mechanism of action, resistance to treatment, and prospects of steroids therapy in pediatric ALL.
Review • Journal • IO biomarker
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BCL2L11 (BCL2 Like 11) • IL7R (Interleukin 7 Receptor) • IL7 (Interleukin 7)
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IL7R mutation
|
prednisone • dexamethasone
2years
A Phase 2 Study of Ruxolitinib With Chemotherapy in Children With Acute Lymphoblastic Leukemia (clinicaltrials.gov)
P2, N=170, Recruiting, Incyte Corporation | Trial primary completion date: Feb 2024 --> Dec 2024
Trial primary completion date
|
JAK2 (Janus kinase 2) • CRLF2 (Cytokine Receptor Like Factor 2) • JAK1 (Janus Kinase 1) • IL7R (Interleukin 7 Receptor) • EPOR (Erythropoietin Receptor) • SH2B3 (SH2B Adaptor Protein 3)
|
CRLF2 rearrangement • JAK2 mutation • IL7R mutation • JAK2 fusion • SH2B3 deletion
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cytarabine • doxorubicin hydrochloride • Jakafi (ruxolitinib) • cyclophosphamide • vincristine • prednisone • leucovorin calcium • Oncaspar liquid (pegaspargase) • mercaptopurine • thioguanine • Erwinase (erwinia L-asparaginase)
2years
An instructive role for Interleukin-7 receptor α in the development of human B-cell precursor leukemia. (PubMed, Nat Commun)
CRISPR mediated gene silencing of CDKN2A in primary human CD34 cells transduced with activated IL7RA results in robust development of BCP-ALLs in-vivo. Thus, we demonstrate that constitutive activation of IL7RA can initiate preleukemia in primary human hematopoietic progenitors and cooperates with CDKN2A silencing in progression into BCP-ALL.
Journal
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CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • CD19 (CD19 Molecule) • CD34 (CD34 molecule) • IL7R (Interleukin 7 Receptor) • IL7 (Interleukin 7)
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CDKN2A deletion • IL7R mutation
over2years
Interleukin-7 receptor α mutational activation can initiate precursor B-cell acute lymphoblastic leukemia. (PubMed, Nat Commun)
Notably, we identify 2 transcriptional subgroups in mouse and human Ph-like ALL, and show that dactolisib and sphingosine-kinase inhibitors are potential treatment avenues for IL-7R-related cases. Our model, a resource to explore the pathophysiology and therapeutic vulnerabilities of B-ALL, demonstrates that IL7R can initiate this malignancy.
Journal • IO biomarker
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BCL2 (B-cell CLL/lymphoma 2) • IKZF1 (IKAROS Family Zinc Finger 1) • PAX5 (Paired Box 5) • IL7R (Interleukin 7 Receptor) • ARID2 (AT-Rich Interaction Domain 2) • STAT5A (Signal Transducer And Activator Of Transcription 5A)
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IL7R mutation • IL7R expression
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dactolisib (RTB101)
over2years
Computational studies reveal co-occurrence of two mutations in IL7R gene of high-grade serous carcinoma patients. (PubMed, J Biomol Struct Dyn)
These comprehensive studies point to a hitherto unexplored significant role of the IL7R gene in ovarian carcinoma. It is envisaged that the work will lay the foundation for the development of a novel biomarker with potential application in molecular profiling and in estimation of the disease prognosis.Communicated by Ramaswamy H. Sarma.
Clinical • Journal
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IL7R (Interleukin 7 Receptor) • FN1 (Fibronectin 1)
|
IL7R mutation
almost3years
A Phase 2 Study of Ruxolitinib With Chemotherapy in Children With Acute Lymphoblastic Leukemia (clinicaltrials.gov)
P2, N=170, Recruiting, Incyte Corporation | Trial completion date: May 2024 --> Dec 2024
Clinical • Trial completion date
|
JAK2 (Janus kinase 2) • CRLF2 (Cytokine Receptor Like Factor 2) • JAK1 (Janus Kinase 1) • IL7R (Interleukin 7 Receptor) • EPOR (Erythropoietin Receptor) • SH2B3 (SH2B Adaptor Protein 3)
|
CRLF2 rearrangement • JAK2 mutation • IL7R mutation • JAK2 fusion • SH2B3 deletion
|
cytarabine • doxorubicin hydrochloride • Jakafi (ruxolitinib) • vincristine • prednisone • leucovorin calcium • Oncaspar liquid (pegaspargase) • mercaptopurine • thioguanine • Erwinase (erwinia L-asparaginase)
3years
[VIRTUAL] IL7R MUTATIONAL ACTIVATION CAN INITIATE PH-LIKE AND PAX5 P80R PRECURSOR B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA (EHA 2021)
Because IL7R mutant leukemias exhibit clear upregulation of mTOR signaling, we administered the clinical-grade dual PI3K and mTOR inhibitor dactolisib and show it has a striking impact on the frequency of leukemia cells in the blood, significantly prolonging mouse survival...Importantly, we validated our findings in IL7R mutant primary human B-ALLs. Conclusion Our studies provide a novel, powerful in vivo resource to explore the pathophysiology and therapeutic vulnerabilities of B-ALL, and demonstrate for the first time that IL7R can initiate this malignancy.
IO biomarker
|
KRAS (KRAS proto-oncogene GTPase) • BCL2 (B-cell CLL/lymphoma 2) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • IKZF1 (IKAROS Family Zinc Finger 1) • JAK1 (Janus Kinase 1) • PAX5 (Paired Box 5) • IL7R (Interleukin 7 Receptor) • ARID2 (AT-Rich Interaction Domain 2)
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KRAS mutation • CDKN2A deletion • CDKN2A mutation • IL7R mutation • PAX5 mutation • KRAS deletion
|
dactolisib (RTB101)
3years
Overexpression of wild type IL-7Rα promotes T-cell acute lymphoblastic leukemia/lymphoma. (PubMed, Blood)
Here, we show that overexpression of IL-7Rα in tetracycline-inducible Il7r transgenic and Rosa26 IL7R knock-in mice drives potential thymocyte self-renewal, and thymus hyperplasia due to increased proliferation of T-cell precursors, which subsequently infiltrate lymph nodes, spleen and bone marrow, ultimately leading to fatal leukemia...Notably, we also find that established tumors may no longer require high levels of IL-7R expression upon secondary transplantation and can progress in the absence of IL-7, but remain sensitive to inhibitors of IL-7R-mediated signaling Ruxolitinib (Jak1), AZD1208 (Pim), Dactolisib (PI3K/mTOR), Palbociclib (Cdk4/6), and Venetoclax (Bcl-2). The relevance of these findings for human disease are highlighted by the fact that T-ALL patient samples with high wild type IL7R expression display a transcriptional signature resembling that from IL-7-stimulated pro-T cells and, critically, from IL7R mutant T-ALL cases. Overall, our studies demonstrate that high expression of IL-7Rα can promote T-cell tumorigenesis even in the absence of IL-7Rα mutational activation.
Journal • IO biomarker
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BCL2 (B-cell CLL/lymphoma 2) • CDK4 (Cyclin-dependent kinase 4) • JAK1 (Janus Kinase 1) • IL7R (Interleukin 7 Receptor)
|
IL7R mutation
|
Venclexta (venetoclax) • Ibrance (palbociclib) • Jakafi (ruxolitinib) • dactolisib (RTB101) • AZD1208
3years
[VIRTUAL] A combination of IL7Rα and NRAS mutations up-regulates Bcl-2 and cMyc levels leading to formation of T-cell acute lymphoblastic leukemia (AACR 2021)
Our results are confirmed by induction of a similar phenotype with a combination of overexpressed WT c-Myc and mutant IL7Rα, which caused severe leukemia as early as 16 days post-transplant. Taken together, we developed a robust model to study T-ALL in mice, shed light on novel pathways of oncogenesis and discovered new targets for intervention that could lead to better therapeutic development.
IO biomarker
|
NRAS (Neuroblastoma RAS viral oncogene homolog) • MYC (V-myc avian myelocytomatosis viral oncogene homolog) • BCL2 (B-cell CLL/lymphoma 2) • IL7R (Interleukin 7 Receptor)
|
NRAS mutation • MYC overexpression • BCL2 expression • MYC expression • IL7R mutation
over3years
[VIRTUAL] The Central Role of MAPK-ERK Signaling in IL7-Dependent and IL7-Independent Steroid Resistance Reveals a Broad Application of MEK-Inhibitors Compared to JAK1/2-Inhibition in T-ALL (ASH 2020)
When we combine prednisolone treatment with selumetinib or ruxolitinib, we observe that ruxolitinib only synergizes with prednisolone in IL7-dependent steroid resistant PDX samples in the presence of IL7. Moreover, our data proposes that this synergistic effect may (in part) depend on the anti-MAPK-ERK effect downstream of JAK1/2-inhibition. Combined, our study strongly supports the enrollment of T-ALL patients in the current phase I/II SeluDex trial (NCT03705507), and contributes to the optimization and stratification of newly designed T-ALL treatment regimens.
IO biomarker
|
NRAS (Neuroblastoma RAS viral oncogene homolog) • BCL2 (B-cell CLL/lymphoma 2) • MCL1 (Myeloid cell leukemia 1) • BCL2L1 (BCL2-like 1) • JAK1 (Janus Kinase 1) • BCL2L11 (BCL2 Like 11) • AURKA (Aurora kinase A) • IL7R (Interleukin 7 Receptor) • STAT5B (Signal Transducer And Activator Of Transcription 5B)
|
NRAS mutation • NRAS overexpression • IL7R mutation • JAK1 overexpression • STAT5B N642H
|
Koselugo (selumetinib) • Jakafi (ruxolitinib) • prednisolone
over3years
[VIRTUAL] Outcomes of Patients with CRLF2-Overexpressing Acute Lymphoblastic Leukemia without Down Syndrome: A Report from the Children’s Oncology Group (ASH 2020)
Development of successful treatment strategies to decrease relapse and to improve survival remains a major therapeutic gap for NCI HR CRLF2+ ALL patients. Current clinical trials are studying the potential efficacy of kinase inhibitor addition to chemotherapy for children, adolescents, and adults with HR Ph-like ALL harboring CRLF2 rearrangements/other JAK pathway alterations or ABL class kinase fusions (NCT0240717, NCT02723994, NCT02883049, NCT03571321).
Clinical
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JAK2 (Janus kinase 2) • CRLF2 (Cytokine Receptor Like Factor 2) • JAK1 (Janus Kinase 1) • IL7R (Interleukin 7 Receptor) • P2RY8 (P2Y Receptor Family Member 8)
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CRLF2 rearrangement • IL7R mutation • P2RY8-CRLF2 fusion • IGH-CRLF2 fusion
over3years
Adult T-cell acute lymphoblastic leukemias with IL7R pathway mutations are slow-responders who do not benefit from allogeneic stem-cell transplantation. (PubMed, Leukemia)
IL7Rp-mutations identify a subgroup of slow-responder T-ALLs which benefit from post-induction chemotherapy regimens but not from HSCT. Our data suggest that prior knowledge of the mutation status of IL7Rp may influence HSCT decision and help to guide therapy reduction.
Clinical • Journal
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NRAS (Neuroblastoma RAS viral oncogene homolog) • JAK1 (Janus Kinase 1) • IL7R (Interleukin 7 Receptor) • JAK3 (Janus Kinase 3) • STAT5B (Signal Transducer And Activator Of Transcription 5B)
|
NRAS mutation • IL7R mutation • JAK3 mutation
4years
Ruxolitinib and Chemotherapy in Adolescents and Young Adults With Ph-like Acute Lymphoblastic Leukemia (clinicaltrials.gov)
P1, N=15, Active, not recruiting, University of Chicago | Not yet recruiting --> Active, not recruiting
Clinical • Enrollment closed • Combination therapy
|
JAK2 (Janus kinase 2) • CRLF2 (Cytokine Receptor Like Factor 2) • IL7R (Interleukin 7 Receptor) • SH2B3 (SH2B Adaptor Protein 3)
|
CRLF2 rearrangement • JAK2 mutation • IL7R mutation • JAK2 rearrangement • SH2B3 deletion
|
Rituxan (rituximab) • cytarabine • doxorubicin hydrochloride • Jakafi (ruxolitinib) • vincristine • Oncaspar liquid (pegaspargase) • mercaptopurine • thioguanine • cyclophosphamide intravenous