Hairy cell leukemia (HCL) is a rare chronic B-cell lymphoproliferative disorder named for its characteristic hair-like cytoplasmic projections from the malignant cells. HCL is classified as an indolent lymphoproliferative neoplasm, representing ~2% of all leukemias with ~1240 new cases diagnosed annually in the US; median age-at-onset is 55 years [1]. It affects males more than females (4:1), and whites more than African-Americans [1]. Although familial and sporadic HCL exhibit similar clinical features, no characteristic germline genetic variation has been found. Familial HCL is rare with fewer than 20 families reported in the literature. Thirteen of the 15 reported pedigrees had two affected individuals; the remaining two pedigrees harbored three, including the family reported here [2,3,4,5]. Investigators have speculated that HCL may be an HLA-linked disorder but, in aggregate, the data are inconclusive [3,4,5]. The discovery that a somatic BRAF mutation (V600E) was nearly universal in HCL (but absent in other B-cell neoplasms) provided major insight into disease biology, identifying a critical therapeutic target [6], but no germline genetic susceptibility variants have been identified. In this study we applied high-throughput sequencing technology to four multiplex HCL pedigrees, seeking to identify shared germline variants conferring HCL susceptibility. In addition, we used CRISPR/Cas9-based genome editing to introduce CASP9 p.H237P, one of the variants shared by all four affected members of the largest pedigree, into a model cell line, followed by measurements of cellular caspase-9 activity and apoptotic response.
Journal
Leukemia, 2020