ArticleBlood2021
CBL mutations drive PI3K/AKT signaling via increased interaction with LYN and PIK3R1.
Article in Blood, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 47 citations in OpenAlex.
- Molecular and clinical analyses of c-CBL mutations affecting tyrosine 371 in myelodysplastic and proliferative disorders.Leukemia · 2026Article
- [Ubiquitination-mediated regulation of T cell homeostasis and autoimmune diseases].Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences · 2026Review
- GATRSyn: Advancing Anticancer Drug Synergy Prediction Through Graph Attention Networks and Transformer-based Feature Re-embedding.Interdisciplinary sciences, computational life sciences · 2026Article
- Tumor suppressor genes and KRAS G12C inhibitor resistance in non-small cell lung cancer.iScience · 2026Review
- Locking CBL TKBD in its native conformation presents a novel therapeutic opportunity in mutant CBL-dependent leukemia.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Article
- Recent progress and future challenges in structure-based protein-protein interaction prediction.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Review
- scPharm: Identifying Pharmacological Subpopulations of Single Cells for Precision Medicine in Cancers.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Autoinflammation in patients with leukocytic CBL loss of heterozygosity is caused by constitutive ERK-mediated monocyte activation.The Journal of clinical investigation · 2024Article
- Exploiting the potential of the ubiquitin-proteasome system in overcoming tyrosine kinase inhibitor resistance in chronic myeloid leukemia.Genes & diseases · 2024Review
- Immunological and hematological findings as major features in a patient with a new germline pathogenic CBL variant.American journal of medical genetics. Part A · 2024Article
- Long non-coding RNA small nucleolar RNA host gene 29 drives chronic myeloid leukemia progression via microRNA-483-3p/Casitas B-lineage Lymphoma axis-mediated activation of the phosphoinositide 3-kinase/Akt pathway.Medical oncology (Northwood, London, England) · 2024Article
- Review
- LncRNA AL645608.3 mediates malignant progression of acute myeloid leukemia.American journal of translational research · 2024Article
- Clinical significance of genetic profiling based on different anatomic sites in patients with mucosal melanoma who received or did not receive immune checkpoint inhibitors.Cancer cell international · 2023Article
- [CBL inhibits proliferation and invasion of breast cancer cells by ubiquitylation-mediated degradation of NCK2].Nan fang yi ke da xue xue bao = Journal of Southern Medical University · 2022Article
- Inhibitory role of proguanil on the growth of bladder cancer via enhancing EGFR degradation and inhibiting its downstream signaling pathway to induce autophagy.Cell death & disease · 2022Article
- Molecular Pathogenesis of Myeloproliferative Neoplasms: From Molecular Landscape to Therapeutic Implications.International journal of molecular sciences · 2022Review
- Review
- Review
- TRPV1 Is a Potential Tumor Suppressor for Its Negative Association with Tumor Proliferation and Positive Association with Antitumor Immune Responses in Pan-Cancer.Journal of oncology · 2022Article
Corrections and comments
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Authors and funding
15 authors at 4 institutions in 1 country.
Funding
Abstract
Casitas B-lineage lymphoma (CBL) encodes an E3 ubiquitin ligase and signaling adaptor that regulates receptor and nonreceptor tyrosine kinases. Recurrent CBL mutations occur in myeloid neoplasms, including 10% to 20% of chronic myelomonocytic leukemia (CMML) cases, and selectively disrupt the protein's E3 ubiquitin ligase activity. CBL mutations have been associated with poor prognosis, but the oncogenic mechanisms and therapeutic implications of CBL mutations remain incompletely understood. We combined functional assays and global mass spectrometry to define the phosphoproteome, CBL interactome, and mechanism of signaling activation in a panel of cell lines expressing an allelic series of CBL mutations. Our analyses revealed that increased LYN activation and interaction with mutant CBL are key drivers of enhanced CBL phosphorylation, phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1) recruitment, and downstream phosphatidylinositol 3-kinase (PI3K)/AKT signaling in CBL-mutant cells. Signaling adaptor domains of CBL, including the tyrosine kinase-binding domain, proline-rich region, and C-terminal phosphotyrosine sites, were all required for the oncogenic function of CBL mutants. Genetic ablation or dasatinib-mediated inhibition of LYN reduced CBL phosphorylation, CBL-PIK3R1 interaction, and PI3K/AKT signaling. Furthermore, we demonstrated in vitro and in vivo antiproliferative efficacy of dasatinib in CBL-mutant cell lines and primary CMML. Overall, these mechanistic insights into the molecular function of CBL mutations provide rationale to explore the therapeutic potential of LYN inhibition in CBL-mutant myeloid malignancies.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.