ArticleThe Journal of biological chemistry2009
Acute lymphoblastic leukemia-associated JAK1 mutants activate the Janus kinase/STAT pathway via interleukin-9 receptor alpha homodimers.
Article in The Journal of biological chemistry, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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Who cites it
43 citing papers in PubMed, 65 citations in OpenAlex.
- T cell lymphomas: cancers of aberrant immune synapse signalling.Nature reviews. Immunology · 2026Review
- Non-receptor tyrosine kinase signaling pathways and therapeutic implications.Signal transduction and targeted therapy · 2026Review
- Malignant JAK-signaling: at the interface of inflammation and malignant transformation.Leukemia · 2025Review
- JAKs and STATs from a Clinical Perspective: Loss-of-Function Mutations, Gain-of-Function Mutations, and Their Multidimensional Consequences.Journal of clinical immunology · 2023Review
- MicroRNAs and JAK/STAT3 signaling: A new promising therapeutic axis in blood cancers.Genes & diseases · 2022Review
- Article
- JAK-STAT core cancer pathway: An integrative cancer interactome analysis.Journal of cellular and molecular medicine · 2022Review
- Oncogenic Cooperation Between IL7R-JAK-STAT Pathway Mutations.HemaSphere · 2021Article
- Deregulation of the Interleukin-7 Signaling Pathway in Lymphoid Malignancies.Pharmaceuticals (Basel, Switzerland) · 2021Review
- Janus Kinase Mutations in Mice Lacking PU.1 and Spi-B Drive B Cell Leukemia through Reactive Oxygen Species-Induced DNA Damage.Molecular and cellular biology · 2020Article
- miR-208b-5p inhibits invasion of non-small cell lung cancer through the STAT3 pathway by targeting interleukin-9.Oncology letters · 2020Article
- Therapeutic targeting of JAKs: from hematology to rheumatology and from the first to the second generation of JAK inhibitors.Mediterranean journal of rheumatology · 2020Review
- IL-9 and IL-9-producing cells in tumor immunity.Cell communication and signaling : CCS · 2020Review
- Clinico-Biological Implications of Modified Levels of Cytokines in Chronic Lymphocytic Leukemia: A Possible Therapeutic Role.Cancers · 2020Review
- Article
- Driver mutations in Janus kinases in a mouse model of B-cell leukemia induced by deletion of PU.1 and Spi-B.Blood advances · 2018Article
- The CCR4-NOT complex is a tumor suppressor in Drosophila melanogaster eye cancer models.Journal of hematology & oncology · 2018Article
- Nonlinear variable selection with continuous outcome: a fully nonparametric incremental forward stagewise approach.Statistical analysis and data mining · 2018Article
- JAK inhibitors for the treatment of myeloproliferative neoplasms and other disorders.F1000Research · 2018Review
- Evaluation of Interleukin-9 Expression as a Potential Therapeutic Target in Chronic Lymphocytic Leukemia in a Cohort of Egyptian Patients.Indian journal of hematology & blood transfusion : an official journal of Indian Society of Hematology and Blood Transfusion · 2017Article
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Authors and funding
8 authors at 3 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Activating mutations in JAK1 have been reported in acute lymphoblastic leukemias, but little is known about the mechanisms involved in their constitutive activation. Here, we studied the ability of JAK1 V658F and A634D to activate the Janus kinase (JAK)/STAT pathway upon ectopic expression in HEK293 cells alone or together with the other components of the interleukin-9 receptor complex (IL-9Ralpha, gammac, and JAK3). Expression of JAK1 mutants alone failed to trigger STAT activation, but co-expression of the IL-9Ralpha chain promoted JAK1 mutant phosphorylation and STAT activation. Mutation of the FERM domain of JAK1, which is critical for cytokine receptor association, or of the single tyrosine of IL-9Ralpha involved in STAT recruitment abolished this activity, indicating that JAK1 mutants need to associate with a functional IL-9Ralpha to activate STAT factors. Several lines of evidence indicated that IL-9Ralpha homodimerization was involved in this process. IL-9Ralpha variants with mutations of the JAK-interacting BOX1 region not only failed to promote JAK1 activation but also acted as dominant negative forms reverting the effect of wild-type IL-9Ralpha. Coimmunoprecipitation experiments also showed the formation of IL-9Ralpha homodimers. Interestingly, STAT activation was partially inhibited by expression of gammac, suggesting that overlapping residues are involved in IL-9Ralpha homodimerization and IL-9Ralpha/gammac heterodimerization. Co-expression of wild-type JAK3 partially reverted the inhibition by gammac, indicating that JAK3 cooperates with JAK1 mutants within the IL-9 receptor complex. Similar results were observed with IL-2Rbeta. Taken together, our results show that IL-9Ralpha and IL-2Rbeta homodimers efficiently mediate constitutive activation of ALL-associated JAK1 mutants.
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