Chronic neutrophilic leukemia in a child with a CSF3R T618I germ line mutation

Abstract

et al. The colony-stimulating factor 3 receptor T640N mutation is oncogenic, sensitive to JAK inhibition, and mimics T618I.

Chronic neutrophilic leukemia: 2020 update on diagnosis, molecular genetics, prognosis, and management

“…There are currently three cases of suspected familial CNL in the literature, though only the most recently described one represents inherited transmission of a constitutional CSF3R T618I mutation confirmed through targeted high throughput sequencing of germline DNA . The authors suggest testing for germline CSF3R status in suspected familial cases in order to define the true prevalence of constitutional CNL.…”

Chronic neutrophilic leukemia: 2018 update on diagnosis, molecular genetics and management

“…In that data set of WHO‐defined CNL, the median age at diagnosis was 66 years (range: 15 – 86) and 56% were male . With the discovery of CSFR3 mutations in CNL, comes the opportunity for greater accuracy in true CNL diagnosis: we performed s review of the literature from that point on (2013) and identified a total 57 reported cases of CSF3R ‐mutated CNL, the majority (88%) carrying the CSF3R T618I mutation . The median age (range) was 65 years (10–92) and 70% were male.…”

“…Since these initial discoveries, several investigators have validated these findings in small series and case reports of WHO‐defined CNL, including the high frequency of activating proximal membrane type point mutations, predominantly CSF3R T618I and the not infrequent co‐occurrence of missense or non‐sense exon 17 truncation mutations, resulting in compound mutations. (Table ) 7, Meggendorfer et al reported six cases of CSF3R ‐mutated CNL, five being CSF3R T618I, of which three carried a compound truncation mutation. Two separate series of CSF3R ‐mutated WHO‐defined CNL from China, each reporting eight cases, had similar findings; one showing all eight patients to carry the CSF3R T618I mutation, the other reporting seven of eight cases with a CSF3R T618I, 2 of which were also compound mutations with truncation mutations .…”

“… Two separate series of CSF3R ‐mutated WHO‐defined CNL from China, each reporting eight cases, had similar findings; one showing all eight patients to carry the CSF3R T618I mutation, the other reporting seven of eight cases with a CSF3R T618I, 2 of which were also compound mutations with truncation mutations . In reviewing the literature reported to date, we identified a total 57 cases of CSF3R ‐mutated CNL . Eighty‐eight percent (50 of 57 cases) carried the CSF3R T618I mutation, either alone (n = 30) or in conjunction with a truncation mutations in 25% of the cases ( n = 10) …”

“…They demonstrated that the CSF3R T640N mutation had properties analogous to those of the T618I mutation, including ligand independence, oncogenicity in cellular transformation assays and in a mouse hematopoietic stem cell transplant model, as well as similar sensitivity to JAK inhibition in vitro using CSF3R T640N transformed cells . In 2016 Druhan et al reported CNL in a child with a CSF3R T618I germ line mutation, although as neither parent carried this mutation, this was felt to have arisen as a result of either genetic mosaicism or as a spontaneous mutation in utero …”