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Ref Type Journal Article
PMID (23656643)
Authors Maxson JE, Gotlib J, Pollyea DA, Fleischman AG, Agarwal A, Eide CA, Bottomly D, Wilmot B, McWeeney SK, Tognon CE, Pond JB, Collins RH, Goueli B, Oh ST, Deininger MW, Chang BH, Loriaux MM, Druker BJ, Tyner JW
Title Oncogenic CSF3R mutations in chronic neutrophilic leukemia and atypical CML.
Journal Vol Issue Date Pages Journal Short Title
The New England journal of medicine 368 19 2013 May 09 1781-90 N Engl J Med
URL
Abstract Text The molecular causes of many hematologic cancers remain unclear. Among these cancers are chronic neutrophilic leukemia (CNL) and atypical (BCR-ABL1-negative) chronic myeloid leukemia (CML), both of which are diagnosed on the basis of neoplastic expansion of granulocytic cells and exclusion of genetic drivers that are known to occur in other myeloproliferative neoplasms and myeloproliferative-myelodysplastic overlap neoplasms.To identify potential genetic drivers in these disorders, we used an integrated approach of deep sequencing coupled with the screening of primary leukemia cells obtained from patients with CNL or atypical CML against panels of tyrosine kinase-specific small interfering RNAs or small-molecule kinase inhibitors. We validated candidate oncogenes using in vitro transformation assays, and drug sensitivities were validated with the use of assays of primary-cell colonies.We identified activating mutations in the gene encoding the receptor for colony-stimulating factor 3 (CSF3R) in 16 of 27 patients (59%) with CNL or atypical CML. These mutations segregate within two distinct regions of CSF3R and lead to preferential downstream kinase signaling through SRC family-TNK2 or JAK kinases and differential sensitivity to kinase inhibitors. A patient with CNL carrying a JAK-activating CSF3R mutation had marked clinical improvement after the administration of the JAK1/2 inhibitor ruxolitinib.Mutations in CSF3R are common in patients with CNL or atypical CML and represent a potentially useful criterion for diagnosing these neoplasms. (Funded by the Leukemia and Lymphoma Society and others.).

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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 Q741* nonsense gain of function CSF3R Q741* results in a premature truncation of the Csf3r protein at amino acid 741 of 836 (UniProt.org). Q741* results in increased Csf3r cell surface expression, impaired receptor internalization, G-CSF hypersensitivity, elevated Stat5 activation, and is transforming in cell culture (PMID: 23656643, PMID: 28439110).
CSF3R S783fs frameshift gain of function - predicted CSF3R S783fs results in a change in the amino acid sequence of the Csf3r protein beginning at aa 783 of 836, likely resulting in premature truncation of the functional protein (UniProt.org). S783fs does not result in increased Stat3 activation (PMID: 23656643, PMID: 24403076), however, results in increased Src activation and transformation in cell culture (PMID: 23656643), and therefore, is predicted to lead to a gain of Csf3r protein function.
CSF3R S783Kfs*6 frameshift gain of function - predicted CSF3R S783Kfs*6 indicates a shift in the reading frame starting at amino acid 783 and terminating 6 residues downstream causing a premature truncation of the 836 amino acid Csf3r protein (UniProt.org). S783Kfs*6 has not been characterized, but is predicted to lead to a gain of Csf3r protein function based on the effects of a similar frameshift mutation at S783 (PMID: 23656643).
CSF3R S783Qfs*6 frameshift gain of function - predicted CSF3R S783Qfs*6 indicates a shift in the reading frame starting at amino acid 783 and terminating 6 residues downstream causing a premature truncation of the 836 amino acid Csf3r protein (UniProt.org). S783Qfs*6 has not been characterized, but is predicted to lead to a gain of Csf3r protein function based on the effects of a similar frameshift mutation at S783 (PMID: 23656643).
CSF3R T615A missense gain of function CSF3R T615A lies within fibronectin type-III domain 5 of the Csf3r protein (PMID: 23656643). T615A confers a gain of function to the Csf3r protein as demonstrated by increased Stat3 phosphorylation and decreased O-linked glycosylation in cultured cells (PMID: 24403076) and transformation in cultured cells (PMID: 23656643, PMID: 24403076).
CSF3R T618I missense gain of function CSF3R T618I lies within the extracellular domain proximal to the transmembrane domain of the Csf3r protein (PMID: 23656643). T618I confers a gain of function to the Csf3r protein as demonstrated by increased proliferation (PMID: 23656643), increased colony formation (PMID: 31784538), increased downstream Jak-Stat signaling in transformed cells in culture (PMID: 23656643), and led to the development of leukemia in a mouse model (PMID: 31784538).
CSF3R Y752* nonsense unknown CSF3R Y752* results in a premature truncation of the Csf3r protein at amino acid 752 of 836 (UniProt.org). Y752* has been identified in the scientific literature (PMID: 23656643), but has not been biochemically characterized and therefore, its effect on Csf3r protein function is unknown (PubMed, Feb 2025).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
CSF3R mutant bone marrow cancer not applicable N/A Clinical Study Emerging In clinical studies, high frequency of CSF3R mutations was identified in patients with chronic neutrophilic leukemia (PMID: 23656643, PMID: 24081659), suggesting that this may serve as a future diagnostic biomarker (PMID: 24441292). 24081659 23656643 24441292
CSF3R S783fs chronic neutrophilic leukemia predicted - resistant Pyridone 6 Preclinical - Patient cell culture Actionable In a preclinical study, cells derived from a patient with chronic neutrophilic leukemia harboring CSF3R S783fs did not respond to treatment with Pyridone 6 (CMP6) in culture (PMID: 23656643). 23656643
CSF3R S783fs chronic neutrophilic leukemia predicted - resistant Tofacitinib Preclinical - Patient cell culture Actionable In a preclinical study, cells derived from a patient with chronic neutrophilic leukemia harboring CSF3R S783fs did not respond to treatment with Xeljanz (tofacitinib) in culture (PMID: 23656643). 23656643
CSF3R S783fs chronic neutrophilic leukemia predicted - resistant Momelotinib Preclinical - Patient cell culture Actionable In a preclinical study, cells derived from a patient with chronic neutrophilic leukemia harboring CSF3R S783fs did not respond to treatment with Momelotinib (CYT387) in culture (PMID: 23656643). 23656643
CSF3R S783fs chronic neutrophilic leukemia predicted - sensitive Dasatinib Preclinical - Patient cell culture Actionable In a preclinical study, cells derived from a patient with chronic neutrophilic leukemia harboring CSF3R S783fs demonstrated sensitive to treatment with Sprycel (dasatinib) in culture (PMID: 23656643). 23656643