Genomic analyses reveal recurrent mutations in epigenetic modifiers and the JAK-STAT pathway in Sézary syndrome.
Genomic analyses reveal recurrent mutations in epigenetic modifiers and the JAK-STAT pathway in Sézary syndrome.
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DOI：
10.1038/ncomms9470
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发表时间：
2015-09-29
影响因子：
16.6
通讯作者：
Elenitoba-Johnson KSJ
中科院分区：
文献类型：
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作者：
Kiel MJ;Sahasrabuddhe AA;Rolland DCM;Velusamy T;Chung F;Schaller M;Bailey NG;Betz BL;Miranda RN;Porcu P;Byrd JC;Medeiros LJ;Kunkel SL;Bahler DW;Lim MS;Elenitoba-Johnson KSJ
Sézary综合征（SS）是一种成熟T细胞的侵袭性白血病，预后不良，靶向治疗选择有限。综合遗传改变的发病机制SS是未知的。在这里，我们整合了全基因组测序（n=6），全外显子组测序（n=66）和阵列比较基因组杂交为基础的拷贝数分析（n=80）的主要SS样品。我们确定了以前未知的复发性功能丧失畸变，靶向染色质重塑/组蛋白修饰和三胸家族的成员，包括ARID 1A，其中在40.3%的SS基因组中观察到无义和移码突变和/或靶向缺失的功能丧失。我们还鉴定了靶向PLCG 1（9%）和JAK 1，JAK 3，STAT 3和STAT 5 B（JAK/STAT总占11%）的复发性功能获得性突变。功能研究揭示JAK 1突变的原代SS细胞对JAK抑制剂治疗的敏感性。这些结果突出了SS的复杂基因组景观和JAK/STAT途径的抑制在SS治疗中的作用。Sézary综合征是一种T细胞恶性肿瘤，在基因组水平上的特征很差。在这项研究中，基尔等人进行了全基因组分析并鉴定了JAK-STAT途径中的突变，并表明原代细胞对JAK抑制剂敏感。
Sézary syndrome (SS) is an aggressive leukaemia of mature T cells with poor prognosis and limited options for targeted therapies. The comprehensive genetic alterations underlying the pathogenesis of SS are unknown. Here we integrate whole-genome sequencing (n=6), whole-exome sequencing (n=66) and array comparative genomic hybridization-based copy-number analysis (n=80) of primary SS samples. We identify previously unknown recurrent loss-of-function aberrations targeting members of the chromatin remodelling/histone modification and trithorax families, including ARID1A in which functional loss from nonsense and frameshift mutations and/or targeted deletions is observed in 40.3% of SS genomes. We also identify recurrent gain-of-function mutations targeting PLCG1 (9%) and JAK1, JAK3, STAT3 and STAT5B (JAK/STAT total ∼11%). Functional studies reveal sensitivity of JAK1-mutated primary SS cells to JAK inhibitor treatment. These results highlight the complex genomic landscape of SS and a role for inhibition of JAK/STAT pathways for the treatment of SS. Sézary syndrome is a T cell malignancy that has been poorly characterized at the genome level. In this study, Kiel et al. perform whole-genome analyses and identify mutations in the JAK–STAT pathway and show that primary cells are sensitive to JAK inhibitors.