Clonal evolution in patients with chronic lymphocytic leukaemia developing resistance to BTK inhibition.
Clonal evolution in patients with chronic lymphocytic leukaemia developing resistance to BTK inhibition.
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慢性淋巴细胞白血病患者对 BTK 抑制产生耐药性的克隆进化
DOI：
10.1038/ncomms11589
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发表时间：
2016-05-20
影响因子：
16.6
通讯作者：
Wu CJ
中科院分区：
文献类型：
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作者：
Burger JA;Landau DA;Taylor-Weiner A;Bozic I;Zhang H;Sarosiek K;Wang L;Stewart C;Fan J;Hoellenriegel J;Sivina M;Dubuc AM;Fraser C;Han Y;Li S;Livak KJ;Zou L;Wan Y;Konoplev S;Sougnez C;Brown JR;Abruzzo LV;Carter SL;Keating MJ;Davids MS;Wierda WG;Cibulskis K;Zenz T;Werner L;Dal Cin P;Kharchencko P;Neuberg D;Kantarjian H;Lander E;Gabriel S;O'Brien S;Letai A;Weitz DA;Nowak MA;Getz G;Wu CJ
对布鲁顿酪氨酸激酶（BTK）抑制剂伊曲替尼的耐药性仅归因于BTK和相关途径分子的突变。使用全外显子组和深度靶向测序，我们剖析了来自5名慢性淋巴细胞白血病患者的系列样本中的伊克替尼耐药性的演变。在两名患者中，我们检测到BTK-C481 S突变或多重PLCG 2突变。其他三名患者表现出携带del（8 p）的克隆扩增，具有额外的驱动突变（EP 300、MLL 2和EIF 2A），其中一名患者发展为CD 19阴性组织细胞肉瘤的转分化。使用液滴微流控技术和生长动力学分析，我们证明了伊替尼耐药亚克隆的存在，并估计治疗开始前的亚克隆大小。TRAIL-R的单倍不足是del（8 p）的结果，导致TRAIL不敏感，这可能导致伊鲁替尼耐药性。这些发现表明，伊布替尼治疗有利于选择和扩增伊布替尼治疗前已经存在的罕见亚克隆，并提供了与伊布替尼耐药相关的遗传变化异质性的见解。 BTK抑制剂伊布替尼用于治疗慢性淋巴细胞白血病，但一些患者对该药物产生耐药性。在这里，作者使用基因组分析来检查5名对伊曲替尼产生耐药性的患者的克隆进化。
Resistance to the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib has been attributed solely to mutations in BTK and related pathway molecules. Using whole-exome and deep-targeted sequencing, we dissect evolution of ibrutinib resistance in serial samples from five chronic lymphocytic leukaemia patients. In two patients, we detect BTK-C481S mutation or multiple PLCG2 mutations. The other three patients exhibit an expansion of clones harbouring del(8p) with additional driver mutations (EP300, MLL2 and EIF2A), with one patient developing trans-differentiation into CD19-negative histiocytic sarcoma. Using droplet-microfluidic technology and growth kinetic analyses, we demonstrate the presence of ibrutinib-resistant subclones and estimate subclone size before treatment initiation. Haploinsufficiency of TRAIL-R, a consequence of del(8p), results in TRAIL insensitivity, which may contribute to ibrutinib resistance. These findings demonstrate that the ibrutinib therapy favours selection and expansion of rare subclones already present before ibrutinib treatment, and provide insight into the heterogeneity of genetic changes associated with ibrutinib resistance. The BTK inhibitor ibrutinib is used to treat chronic lymphocytic leukaemia, however some patients develop resistance to the drug. Here, the authors use genomic analyses to examine the clonal evolution of 5 patients that develop resistance to ibrutinib.