ArticleClinical cancer research : an official journal of the American Association for Cancer Research2016
The Colony-Stimulating Factor 3 Receptor T640N Mutation Is Oncogenic, Sensitive to JAK Inhibition, and Mimics T618I.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 47 citations in OpenAlex.
- Efficacy of Ruxolitinib in Patients With Chronic Neutrophilic Leukemia and Atypical Chronic Myeloid Leukemia.Journal of clinical oncology : official journal of the American Society of Clinical Oncology · 2020Trial
- Colony-Stimulating Factor 3 Receptor Mutations and Variants in Hematological Malignancies.Cancers · 2025Review
- Research progress on the mechanisms of CSF3R mutations in leukemogenesis and treatment strategies.Cancer cell international · 2025Review
- Pan-Cancer Profiling of Intron Retention and Its Clinical Significance in Diagnosis and Prognosis.Cancers · 2023Article
- GermlineInternational journal of molecular sciences · 2023Article
- Chronic neutrophilic leukemia preceded by myelodysplastic syndromes.International journal of hematology · 2023Article
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- Case report: Chronic neutrophilic leukemia associated with monoclonal gammopathies. A case series and review of genetic characteristics and practical management.Frontiers in oncology · 2022Article
- Atypical Chronic Myeloid Leukemia: New Developments from Molecular Diagnosis to Treatment.Medicina (Kaunas, Lithuania) · 2021Review
- Colony-stimulating factor 3 receptor (CSF3R) M696T mutation does not impact on clinical outcomes of a Ph+ acute lymphoblastic leukemia patient.Blood science (Baltimore, Md.) · 2021Article
- When Glycosylation Meets Blood Cells: A Glance of the Aberrant Glycosylation in Hematological Malignancies.Reviews of physiology, biochemistry and pharmacology · 2021Review
- Heterozygous germ line CSF3R variants as risk alleles for development of hematologic malignancies.Blood advances · 2020Article
- Atypical Chronic Myeloid Leukemia: Where Are We Now?International journal of molecular sciences · 2020Review
- Discovery and characterization of targetable NTRK point mutations in hematologic neoplasms.Blood · 2020Article
- Altered expression of CSF3R splice variants impacts signal response and is associated with SRSF2 mutations.Leukemia · 2020Article
- Activating mutations in CSF1R and additional receptor tyrosine kinases in histiocytic neoplasms.Nature medicine · 2019Article
- Mechanisms of Progression of Myeloid Preleukemia to Transformed Myeloid Leukemia in Children with Down Syndrome.Cancer cell · 2019Article
- A Novel Germline Variant in CSF3R Reduces N-Glycosylation and Exerts Potent Oncogenic Effects in Leukemia.Cancer research · 2018Article
- Gain-of-function mutations in granulocyte colony-stimulating factor receptor (CSF3R) reveal distinct mechanisms of CSF3R activation.The Journal of biological chemistry · 2018Article
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Authors and funding
13 authors at 4 institutions in 1 country.
Funding
Abstract
purposeColony-stimulating factor 3 receptor (CSF3R) mutations have been identified in the majority of chronic neutrophilic leukemia (CNL) and a smaller percentage of atypical chronic myeloid leukemia (aCML) cases. Although CSF3R point mutations (e.g., T618I) are emerging as key players in CNL/aCML, the significance of rarer CSF3R mutations is unknown. In this study, we assess the importance of the CSF3R T640N mutation as a marker of CNL/aCML and potential therapeutic target. EXPERIMENTAL
designSanger sequencing of leukemia samples was performed to identify CSF3R mutations in CNL and aCML. The oncogenicity of the CSF3R T640N mutation relative to the T618I mutation was assessed by cytokine independent growth assays and by mouse bone marrow transplant. Receptor dimerization and O-glycosylation of the mutants was assessed by Western blot, and JAK inhibitor sensitivity was assessed by colony assay.
resultsHere, we identify a CSF3R T640N mutation in two patients with CNL/aCML, one of whom was originally diagnosed with MDS and acquired the T640N mutation upon evolution of disease to aCML. The T640N mutation is oncogenic in cellular transformation assays and an in vivo mouse bone marrow transplantation model. It exhibits many similar phenotypic features to T618I, including ligand independence and altered patterns of O-glycosylation--despite the transmembrane location of T640 preventing access by GalNAc transferase enzymes. Cells transformed by the T640N mutation are sensitive to JAK kinase inhibition to a similar degree as cells transformed by CSF3R T618I.
conclusionsBecause of its similarities to CSF3R T618I, the T640N mutation likely has diagnostic and therapeutic relevance in CNL/aCML.
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