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Ref Type Journal Article
PMID (26475333)
Authors Maxson JE, Luty SB, MacManiman JD, Paik JC, Gotlib J, Greenberg P, Bahamadi S, Savage SL, Abel ML, Eide CA, Loriaux MM, Stevens EA, Tyner JW
Title The Colony-Stimulating Factor 3 Receptor T640N Mutation Is Oncogenic, Sensitive to JAK Inhibition, and Mimics T618I.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 22
Issue 3
Date 2016 Feb 01
Abstract Text Colony-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.Sanger 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.Here, 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.Because of its similarities to CSF3R T618I, the T640N mutation likely has diagnostic and therapeutic relevance in CNL/aCML.


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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
CSF3R E808K missense unknown CSF3R E808K lies within the cytoplasmic domain of the Csf3r protein ( E808K (also referred to as E785K) results in decreased colony formation compared to wild-type Csf3r in cultured cells, however, does not alter activation of Erk2, Mapk, Jnk, or Stat5, or cell differentiation (PMID: 15644419), and is not transforming in cell culture (PMID: 26475333), and therefore, its effect on Csf3r protein function is unknown.
CSF3R T640N missense gain of function CSF3R T640N lies within the transmembrane domain of the Csf3r protein ( T640N results in transformation of cells, increased Jak-Stat activation, and tumor growth in mouse models (PMID: 26475333).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
CSF3R T640N Advanced Solid Tumor sensitive Ruxolitinib Preclinical Actionable In a preclinical study, Jakafi (ruxolitinib) reduces colony formation of cells expressing CSF3R T640N in culture (PMID: 26475333). 26475333
CSF3R T618I Advanced Solid Tumor sensitive Ruxolitinib Preclinical - Cell culture Actionable In a preclinical study, Jakafi (ruxolitinib) reduced colony formation of cells expressing CSF3R T618I in culture (PMID: 26475333, PMID: 29977015). 26475333 29977015