Genomic analysis of hairy cell leukemia identifies novel recurrent genetic alterations.

Classical hairy cell leukemia (cHCL) is characterized by a near 100% frequency of the V600E mutation, whereas ∼30% of variant HCLs (vHCLs) have mutations. However, recurrent genetic alterations cooperating with V600E or mutations in HCL, as well as those in wild-type vHCL, are not well defined. We therefore performed deep targeted mutational and copy number analysis of cHCL (n = 53) and vHCL (n = 8). The most common genetic alteration in cHCL apart from V600E was heterozygous loss of chromosome 7q, the minimally deleted region of which targeted wild-type , subdividing cHCL into those hemizygous versus heterozygous for the V600E mutation. In addition to mutations in cHCL, recurrent inactivating mutations in () were identified in 15% and 25% of cHCLs and vHCLs, respectively. Moreover, 13% of vHCLs harbored predicted activating mutations in A change-of-function mutation in the splicing factor was also present in 13% of vHCLs. Genomic analysis of de novo vemurafenib-resistant cHCL identified a novel gain-of-function mutation in and losses of and each of which contributed to resistance. These data provide further insight into the genetic bases of cHCL and vHCL and mechanisms of RAF inhibitor resistance encountered clinically.