Molecular markers
CSF3R
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PubMed Search: CSF3R
Table of Contents
Definition / general | Essential features | Terminology | Pathophysiology | Diagrams / tables | Clinical features | Uses by pathologists | Prognostic factors | Molecular / cytogenetics description | Molecular / cytogenetics images | Sample pathology report | Board review style question #1 | Board review style answer #1Cite this page: Chen Wongworawat Y, Fisher KE. CSF3R. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/molecularCSF3R.html. Accessed April 25th, 2024.
Definition / general
- Colony stimulating factor 3 receptor (NIH: CSF3R [Accessed 23 June 2022])
- The CS3FR gene (NM_172313.3) is located on chromosome 1p34.3 and contains 18 exons
- CS3FR encodes the receptor for colony stimulating factor 3, a cytokine that controls the production, differentiation and function of granulocytes (NIH: CSF3R [Accessed 23 June 2022])
- The encoded protein, which is a member of the family of cytokine receptors, may also function in some cell surface adhesion or recognition processes (NIH: CSF3R [Accessed 23 June 2022])
Essential features
- Somatic activating mutations in CSF3R are the most frequent molecular alteration in patients with chronic neutrophilic leukemia (CNL), seen in > 60% of cases
- The most common somatic activating mutation in CNL is the CSF3R p.Thr618Ile (p.T618I) mutation
- Presence of a somatic CSF3R p.T618I mutation or other somatic activating CSF3R mutations are a major diagnostic criterion for the diagnosis of CNL
- Activating somatic mutations in CSF3R are also observed in various other myeloid malignancies, including atypical chronic myeloid leukemia, acute myeloid leukemia and myelodysplastic syndrome
Terminology
- Granulocyte colony stimulating factor receptor (GCSFR)
- CD114 (transmembrane receptor protein encoded by the CSF3R gene)
- Severe congenital neutropenia 7 (SCN7)
Pathophysiology
- Activating mutations in CSF3R localize to 2 distinct protein domains
- Missense mutations (e.g., p.T615A and p.T618I) cluster in the CSF3R proximal membrane domain and preferentially activate downstream signaling through the JAK / STAT pathway (N Engl J Med 2013;368:1781)
- Loss of function mutations cluster in the C terminus between amino acids p.Y727 and p.Y752, leading to loss of conserved tyrosine residues at positions 727, 752, 767 and 787 and dysregulated signaling through SRC family TNK2 kinases (Ann N Y Acad Sci 2016;1370:119)
Diagrams / tables
Images hosted on other servers:
CSF3R, domains, mutations
Activation, signaling, CSF3R, model
Clinical features
- Inherited / germline mutations in this gene are associated with autosomal dominant hereditary neutrophilia and autosomal recessive severe congenital neutropenia 7 (OMIM: Neutrophilia, Hereditary [Accessed 23 June 2022], OMIM: Neutropenia, Severe Congenital, 7, Autosomal Recessive; SCN7 [Accessed 23 June 2022])
- Acquired CSF3R mutations are implicated in the leukemogenesis of severe congenital neutropenia (Kostmann syndrome) to acute leukemia or myelodysplastic syndrome (Blood 2007;109:93, Front Immunol 2019;10:116)
Uses by pathologists
- Somatic activating mutations in CSF3R are the most frequent molecular alteration detected in patients with chronic neutrophilic leukemia (CNL), seen in > 60% of cases (Blood Cancer J 2018;8:19, N Engl J Med 2013;368:1781)
- Presence of a somatic CSF3R p.T618I mutation or other somatic activating CSF3R mutation is a major criterion for the diagnosis of CNL; however, its absence does not exclude the diagnosis of CNL
- Presence of a CSF3R activating mutation in cases of atypical CML should be morphologically reviewed and, if necessary, recategorized as CNL (Blood 2022 Jun 29 [Epub ahead of print])
Prognostic factors
- Coexistence of CSF3R and ASXL1 mutations is associated with a poorer prognosis in CNL (Am J Hematol 2015;90:653)
- Co-occurrence of SETBP1 mutations with CSF3R p.T618I has been consistently reported in CNL but the prognostic significance is controversial (Front Oncol 2022;12:891961)
Molecular / cytogenetics description
- Detection of CSF3R activating mutations requires sequencing based methods, such as Sanger sequencing, next generation sequencing or pyrosequencing
- Testing of a constitutional sample, such as cultured skin fibroblasts, is required to assess for CSF3R mutations in familial CNL (Blood 2016;128:2097)
Molecular / cytogenetics images
Contributed by Kevin E. Fisher, M.D., Ph.D.
CSF3R, p.T618I, NGS, IGV
Images hosted on other servers:
Sanger, CSF3R, missense, nonsense
Sample pathology report
- Bone marrow, targeted next generation sequencing:
- CSF3R p.T618I missense mutation detected (see comment)
- Comment: Targeted next generation sequencing of the bone marrow sample revealed a p.Thr618Ile missense variant in the CSF3R (colony stimulating factor 3 receptor) gene at a variant allele fraction (VAF) of 43.1%. CSF3R encodes the receptor for colony stimulating factor 3, a cytokine that controls the production, differentiation and function of granulocytes. CSF3R activating mutations, such as the CSF3R p.T618I, are seen in > 60% of patients with chronic neutrophilic leukemia (CNL). In the appropriate clinical and histopathologic context, the presence of a CSF3R activating mutation is considered a major diagnostic criterion for this entity. Clinical and histopathologic correlation is recommended.
Board review style question #1
Next generation sequencing was performed as part of the diagnostic work up for bone marrow hypercellularity and the results are shown in the figure above. This finding is considered a diagnostic marker for which of the following?
- Chronic myeloid leukemia
- Chronic neutrophilic leukemia
- Juvenile myelomonocytic leukemia
- Polycythemia vera
- Systemic mastocytosis
Board review style answer #1
B. Chronic neutrophilic leukemia. This integrative genomics viewer image provides a visual representation of a single nucleotide variant (G > A) in a threonine within the CSF3R gene. CSF3R activating mutations, such as the CSF3R p.T618I, are seen in > 60% of patients with chronic neutrophilic leukemia and the presence of a CSF3R activating mutation is a major diagnostic criterion for this entity. Chronic myeloid leukemia is characterized by BCR::ABL1 fusions detected primarily by Giemsa banding (G banding), fluorescent in situ hybridization (FISH) or reverse transcriptase PCR (RT PCR). The KIT p.D816V mutation is present in the vast majority of typical indolent systemic mastocytosis cases. Juvenile myelomonocytic leukemias typically harbor mutations in RAS pathway genes, such as CBL, KRAS, NF1, NRAS or PTPN11. Polycythemia vera is characteristically associated with mutation of the JAK2 gene.
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Reference: CSF3R
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Reference: CSF3R
