Durham Benjamin H, Getta Bartlomiej, Dietrich Sascha, Taylor Justin, Won Helen, Bogenberger James M, Scott Sasinya, Kim Eunhee, Chung Young Rock, Chung Stephen S, Hüllein Jennifer, Walther Tatjana, Wang Lu, Lu Sydney X, Oakes Christopher C, Tibes Raoul, Haferlach Torsten, Taylor Barry S, Tallman Martin S, Berger Michael F, Park Jae H, Zenz Thorsten, Abdel-Wahab Omar
Department of Pathology and.
Leukemia Service, Memorial Sloan-Kettering Cancer Center, New York, NY.
Blood. 2017 Oct 5;130(14):1644-1648. doi: 10.1182/blood-2017-01-765107. Epub 2017 Aug 11.
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.
经典型毛细胞白血病（cHCL）的特征是V600E突变频率接近100%，而约30%的变异型毛细胞白血病（vHCL）存在突变。然而，与HCL中的V600E或突变协同作用的复发性基因改变，以及野生型vHCL中的那些改变，目前尚未明确。因此，我们对cHCL（n = 53）和vHCL（n = 8）进行了深度靶向突变和拷贝数分析。除V600E外，cHCL中最常见的基因改变是7号染色体长臂杂合性缺失，其最小缺失区域靶向野生型，将cHCL细分为V600E突变半合子与杂合子。除了cHCL中的突变外，分别在15%和25%的cHCL和vHCL中鉴定出了复发性失活突变（）。此外，13%的vHCL在中存在预测的激活突变。13%的vHCL中还存在剪接因子的功能改变突变。对初治的维莫非尼耐药cHCL进行基因组分析，发现中存在一种新的功能获得性突变，以及和的缺失，每一种都导致了耐药。这些数据为cHCL和vHCL的遗传基础以及临床上遇到的RAF抑制剂耐药机制提供了进一步的见解。
