Hypermorphic mutation of phospholipase C, γ2 acquired in ibrutinib-resistant CLL confers BTK independency upon B-cell receptor activation
Hypermorphic mutation of phospholipase C, γ2 acquired in ibrutinib-resistant CLL confers BTK independency upon B-cell receptor activation
复制标题
DOI：
10.1182/blood-2015-02-626846
复制
发表时间：
2015-07-02
期刊：
影响因子：
20.3
通讯作者：
Johnson, Amy J.
中科院分区：
文献类型：
--
作者：
Liu, Ta-Ming;Woyach, Jennifer A.;Johnson, Amy J.
伊布鲁替尼显著改善了复发性慢性淋巴细胞白血病(CLL)患者的预后。最近的报告将伊布鲁替尼的耐药性归因于伊布鲁替尼的靶标Bruton无丙种球蛋白血症酪氨酸激酶(BTK)以及直接下游效应因子磷脂酶C，伽玛2(PLCG2)的获得性突变。尽管在BTK中发现的C481S突变已被证明使ibrutinib不可逆转地结合这一主要靶点的能力丧失，但PLCG2突变的详细机制尚未建立。在这里，我们描述了PLCG2突变R665W的增强的信号能力、BTK独立性和表面免疫球蛋白依赖性，这已在易卜拉替尼耐药的CLL中被记录。我们的数据表明，这种错义改变在B细胞受体参与后引起BTK非依赖性激活，暗示形成了一种新的BTK旁路途径。与先前的结果一致，PLCG2 R665W赋予下游信号事件的超形态诱导。我们的研究表明，近端激酶SYK和Lyn对突变的PLCG2的激活至关重要，针对SYK和Lyn的治疗药物可以对抗伊布鲁替尼耐药患者的细胞系模型和原代CLL细胞中的分子耐药性。总之，我们的结果产生了对PLCG2已识别的异常的分子理解，并探索了其对BTK、SYK和LYN的功能依赖性，从而提出了对抗获得性伊布鲁替尼耐药性的替代策略。
Ibrutinib has significantly improved the outcome of patients with relapsed chronic lymphocytic leukemia (CLL). Recent reports attribute ibrutinib resistance to acquired mutations in Bruton agammaglobulinemia tyrosine kinase (BTK), the target of ibrutinib, as well as the immediate downstream effector phospholipase C, gamma 2 (PLCG2). Although the C481S mutation found in BTK has been shown to disable ibrutinib's capacity to irreversibly bind this primary target, the detailed mechanisms of mutations in PLCG2 have yet to be established. Herein, we characterize the enhanced signaling competence, BTKindependence, and surface immunoglobulin dependence of the PLCG2 mutation at R665W, which has been documented in ibrutinib-resistant CLL. Our data demonstrate that this missense alteration elicits BTK-independent activation after B-cell receptor engagement, implying the formation of a novel BTK-bypass pathway. Consistent with previous results, PLCG2 R665W confers hypermorphic induction of downstream signaling events. Our studies reveal that proximal kinases SYK and LYN are critical for the activation of mutant PLCG2 and that therapeutics targeting SYK and LYN can combat molecular resistance in cell line models and primary CLL cells from ibrutinib-resistant patients. Altogether, our results engender a molecular understanding of the identified aberration at PLCG2and explore its functional dependency on BTK, SYK, and LYN, suggesting alternative strategies to combat acquired ibrutinib resistance.