Diverse and Targetable Kinase Alterations Drive Histiocytic Neoplasms.
Diverse and Targetable Kinase Alterations Drive Histiocytic Neoplasms.
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DOI：
10.1158/2159-8290.cd-15-0913
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发表时间：
2016-02
期刊：
影响因子：
28.2
通讯作者：
Abdel-Wahab O
中科院分区：
文献类型：
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作者：
Diamond EL;Durham BH;Haroche J;Yao Z;Ma J;Parikh SA;Wang Z;Choi J;Kim E;Cohen-Aubart F;Lee SC;Gao Y;Micol JB;Campbell P;Walsh MP;Sylvester B;Dolgalev I;Aminova O;Heguy A;Zappile P;Nakitandwe J;Ganzel C;Dalton JD;Ellison DW;Estrada-Veras J;Lacouture M;Gahl WA;Stephens PJ;Miller VA;Ross JS;Ali SM;Briggs SR;Fasan O;Block J;Héritier S;Donadieu J;Solit DB;Hyman DM;Baselga J;Janku F;Taylor BS;Park CY;Amoura Z;Dogan A;Emile JF;Rosen N;Gruber TA;Abdel-Wahab O
组织细胞肿瘤是克隆性造血系统疾病，其特征分别是在朗格汉斯细胞组织细胞增生症（LCH）和非朗格汉斯细胞组织细胞增生症（non - LCH）中异常的单核细胞衍生的树突状细胞或巨噬细胞的积聚。在约50%的这些患者中发现BRAF V600E突变，为组织细胞增生症提供了首个分子治疗靶点。然而，大多数BRAF V600E野生型非 - LCH患者的复发性驱动突变尚不清楚，并且组织细胞肿瘤中非 - MAP激酶通路的复发性协同突变尚未明确。通过全外显子组和转录组联合测序，我们在BRAF V600E野生型非 - LCH患者中鉴定出涉及BRAF、ALK和NTRK1的复发性激酶融合，以及复发性的激活MAP2K1和ARAF突变。除了MAP激酶通路病变外，还鉴定出涉及多种细胞通路的反复改变的基因。分别使用MEK抑制剂和RAF抑制剂治疗MAP2K1突变和ARAF突变的非 - LCH患者，产生了临床疗效，这表明在这些疾病中检测和靶向多种激酶改变的重要性。
Histiocytic neoplasms are clonal, hematopoietic disorders characterized by an accumulation of abnormal, monocyte-derived dendritic cells or macrophages in Langerhans Cell (LCH) and non-Langerhans (non-LCH) histiocytoses, respectively. The discovery of BRAFV600E mutations in ~50% of these patients provided the first molecular therapeutisc target in histiocytosis. However, recurrent driving mutations in the majority of BRAFV600E-wildtype, non-LCH patients are unknown, and recurrent cooperating mutations in non-MAP kinase pathways are undefined for the histiocytic neoplasms. Through combined whole exome and transcriptome sequencing, we identified recurrent kinase fusions involving BRAF, ALK, and NTRK1, as well as recurrent, activating MAP2K1 and ARAF mutations in BRAFV600E-wildtype, non-LCH patients. In addition to MAP kinase pathway lesions, recurrently altered genes involving diverse cellular pathways were identified. Treatment of MAP2K1- and ARAF-mutated, non-LCH patients using MEK and RAF inhibitors, respectively, resulted in clinical efficacy demonstrating the importance of detecting and targeting diverse kinase alterations in these disorders.