CSF3R Variants

Variants in the CSF3R gene have been reported in 89% of cases of chronic neutrophilic leukaemia, 40% of cases of atypical (BCR-ABL1–negative) CML and 1% of AML (Maxson et al. 2013 NEJM 368,19:1781-1790 and  Gotlib et al. 2013 Blood 122,10:1707-1711). CSF3R variants segregate within two distinct regions of the CSF3R gene (exons 14 and 17), resulting in differential downstream kinase signalling and kinase inhibitor sensitivity. The dominant mode of signalling for patients with single nucleotide variants in exon 14 of CSF3R (membrane proximal variants) is through the JAK–STAT pathway, as a result these patients may be candidates for treatment with JAK kinase inhibitors, such as ruxolitinib. Variants in exon 17 of CSF3R (truncation variants) have been reported to dysregulate SRC family–TNK2 kinases and as a result are sensitive to treatment with dasatinib. CSF3R truncation variants have also been described in patients with congenital neutropenia that progresses to AML after long-term treatment with granulocyte colony-stimulating factor. Detection of a CSF3R variant would therefore support a diagnosis of chronic neutrophilic leukaemia or atypical CML and provide information to allow the selection of an appropriate kinase inhibitor treatment.

CSF3R variants are identified by bi-directional Sanger sequencing of exons 14 and 17 of the CSF3R gene, which will detect variants present at a level of greater than 10%.

Laboratory contact:  Dr. Caroline Wickham 01392 408252

Clinical contact: Dr. Paul Kerr 01392 402917