Genomic analysis of hairy cell leukemia identifies novel recurrent genetic alterations

Abstract

Classical hairy cell leukemia (cHCL) is characterized by a near 100% frequency of the <i>BRAF</i>V600E mutation, whereas ∼30% of variant HCLs (vHCLs) have <i>MAP2K1</i> mutations. However, recurrent genetic alterations cooperating with <i>BRAF</i>V600E or <i>MAP2K1</i> mutations in HCL, as well as those in <i>MAP2K1</i> 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 <i>BRAF</i>V600E was heterozygous loss of chromosome 7q, the minimally deleted region of which targeted wild-type <i>BRAF</i>, subdividing cHCL into those hemizygous versus heterozygous for the <i>BRAF</i>V600E mutation. In addition to <i>CDKN1B</i> mutations in cHCL, recurrent inactivating mutations in <i>KMT2C</i> (<i>MLL3</i>) were identified in 15% and 25% of cHCLs and vHCLs, respectively. Moreover, 13% of vHCLs harbored predicted activating mutations in <i>CCND3</i> A change-of-function mutation in the splicing factor <i>U2AF1</i> was also present in 13% of vHCLs. Genomic analysis of de novo vemurafenib-resistant cHCL identified a novel gain-of-function mutation in <i>IRS1</i> and losses of <i>NF1</i> and <i>NF2,</i> 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.