Genomic analysis of hairy cell leukemia identifies novel recurrent genetic alterations
Genomic analysis of hairy cell leukemia identifies novel recurrent genetic alterations
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DOI：
10.1182/blood-2017-01765107
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发表时间：
2017-10-05
期刊：
影响因子：
20.3
通讯作者：
Abdel-Wahab, Omar
中科院分区：
文献类型：
--
作者：
Durham, Benjamin H.;Getta, Bartlomiej;Abdel-Wahab, Omar
经典毛细胞白血病(CHCL)的特点是BRAFV600E突变的频率接近100%，而变异型毛细胞白血病(VHCL)类似于30%的MAP2K1突变。然而，与HCL中的BRAFV600E或MAP2K1突变以及MAP2K1野生型vHCL中的BRAFV600E或MAP2K1突变协同作用的反复遗传改变并未得到很好的定义。因此，我们对chcl(N553)和vhcl(N58)进行了深度靶向突变和拷贝数分析。除BRAFV600E外，cHCL最常见的遗传改变是7q染色体的杂合性丢失，其最小缺失区域针对野生型BRAF，对于BRAFV600E突变将cHCL细分为半合子和杂合子。除cHCL的CDKN1B突变外，在15%的cHCL和25%的vHCL中分别发现了KMT2C(MLL3)的反复失活突变。此外，13%的vHC预测了CCND3的激活突变。剪接因子U2AF1的功能突变也存在于13%的vHCL中。对耐新维莫拉非尼的cHCL的基因组分析发现，在IRS1中发现了一种新的功能获得突变以及NF1和NF2的丢失，这两种突变中的每一种都与耐药性有关。这些数据为进一步了解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。
Classical hairy cell leukemia (cHCL) is characterized by a near 100% frequency of the BRAFV600E mutation, whereas similar to 30% of variant HCLs (vHCLs) have MAP2K1 mutations. However, recurrent genetic alterations cooperating with BRAFV600E or MAP2K1 mutations in HCL, as well as those in MAP2K1 wild-type vHCL, are not well defined. We therefore performed deep targeted mutational and copy number analysis of cHCL (n553) and vHCL (n 5 8). The most common genetic alteration in cHCL apart from BRAFV600E washeterozygous loss of chromosome7q, the minimally deleted region of which targeted wild-type BRAF, subdividing cHCL into those hemizygous versus heterozygous for the BRAFV600E mutation. In addition to CDKN1B mutations in cHCL, recurrent inactivating mutations in KMT2C (MLL3) were identified in 15% and 25% of cHCLs and vHCLs, respectively. Moreover, 13% ofvHCLsharbored predicted activating mutations inCCND3. Achange-of-function mutation in the splicing factorU2AF1was also present in13% of vHCLs. Genomic analysis of de novo vemurafenib-resistant cHCL identified a novel gain-of-function mutation in IRS1 and losses of NF1 and NF2, each ofwhich contributed to resistance. These data provide further insight into the genetic bases of cHCL and vHCL and mechanisms of RAF inhibitor resistance encountered clinically.