ArticleThe Journal of biological chemistry2010
Novel oncogenic mutations of CBL in human acute myeloid leukemia that activate growth and survival pathways depend on increased metabolism.
Article in The Journal of biological chemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 54 citations in OpenAlex.
- Somatic deficiency of the human E3 ubiquitin ligase CBL in leukocytes impairs B cell but not T cell development and function.Nature immunology · 2026Article
- 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
- The expanding role of the receptor tyrosine kinase MET as a therapeutic target in non-small cell lung cancer.Cell reports. Medicine · 2025Review
- Article
- Dual specific STAT3/5 degraders effectively block acute myeloid leukemia and natural killer/T cell lymphoma.HemaSphere · 2024Article
- A microglia clonal inflammatory disorder in Alzheimer's Disease.bioRxiv : the preprint server for biology · 2024Article
- LncRNA AL645608.3 mediates malignant progression of acute myeloid leukemia.American journal of translational research · 2024Article
- Spatial promoter-enhancer hubs in cancer: organization, regulation, and function.Trends in cancer · 2023Review
- Cell origin-dependent cooperativity of mutant Dnmt3a and Npm1 in clonal hematopoiesis and myeloid malignancy.Blood advances · 2022Article
- Acetylation, Phosphorylation, Ubiquitination (Oh My!): Following Post-Translational Modifications on the Ubiquitin Road.Biomolecules · 2022Review
- Management and Outcomes of Blast Transformed Chronic Myelomonocytic Leukemia.Current hematologic malignancy reports · 2021Review
- Article
- E3 ligase-inactivation rewires CBL interactome to elicit oncogenesis by hijacking RTK-CBL-CIN85 axis.Oncogene · 2021Article
- Inhibition of the deubiquitinase USP10 induces degradation of SYK.British journal of cancer · 2020Article
- The combination of FLT3 and SYK kinase inhibitors is toxic to leukaemia cells with CBL mutations.Journal of cellular and molecular medicine · 2020Article
- Comparison of effects of midostaurin, crenolanib, quizartinib, gilteritinib, sorafenib and BLU-285 on oncogenic mutants of KIT, CBL and FLT3 in haematological malignancies.British journal of haematology · 2019Article
- Cdc42: A Novel Regulator of Insulin Secretion and Diabetes-Associated Diseases.International journal of molecular sciences · 2019Review
- De novo activating mutations drive clonal evolution and enhance clonal fitness in KMT2A-rearranged leukemia.Nature communications · 2018Article
- Structural Determinants of the Gain-of-Function Phenotype of Human Leukemia-associated Mutant CBL Oncogene.The Journal of biological chemistry · 2017Article
- Article
Corrections and comments
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Authors and funding
13 authors at 4 institutions in 2 countries.
Funding
Abstract
Acute myeloid leukemia (AML) is characterized by multiple mutagenic events that affect proliferation, survival, as well as differentiation. Recently, gain-of-function mutations in the α helical structure within the linker sequence of the E3 ubiquitin ligase CBL have been associated with AML. We identified four novel CBL mutations, including a point mutation (Y371H) and a putative splice site mutation in AML specimens. Characterization of these two CBL mutants revealed that coexpression with the receptor tyrosine kinases FLT3 (Fms-like tyrosine kinase 3) or KIT-induced ligand independent growth or ligand hyperresponsiveness, respectively. Growth of cells expressing mutant CBL required expression and kinase activity of FLT3. In addition to the CBL-dependent phosphorylation of FLT3 and CBL itself, transformation was associated with activation of Akt and STAT5 and required functional expression of the small GTPases Rho, Rac, and Cdc42. Furthermore, the mutations led to constitutively elevated intracellular reactive oxygen species levels, which is commonly linked to increased glucose metabolism in cancer cells. Inhibition of hexokinase with 2-deoxyglucose blocked the transforming activity of CBL mutants and reduced activation of signaling mechanisms. Overall, our data demonstrate that mutations of CBL alter cellular biology at multiple levels and require not only the activation of receptor proximal signaling events but also an increase in cellular glucose metabolism. Pathways that are activated by CBL gain-of-function mutations can be efficiently targeted by small molecule drugs.
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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.