Role of BCL10 somatic mutations in lymphomagenesis and response to BCR-targeted therapies

BCL 10体细胞突变在淋巴瘤发生和BCR靶向治疗反应中的作用 摘要 弥漫性大B细胞淋巴瘤（DLBCL）是最常见的淋巴系统恶性肿瘤， 异质性疾病最近两项大型DLBCL患者系列的基因组分析研究将这些 五个不同基因组的患者。这两项研究基本上同意他们的分类，并描述了一个 以前未被注意的亚型，使人联想到边缘区淋巴瘤（MZL），即C1或BN 2淋巴瘤。 这种C1/BN 2亚型的特征在于BCL 6的频繁易位和NOTCH 2的激活突变 和NF-κB信号转导基因。在后者中，30%的患者显示BCL 10突变，这是罕见的 在其他DLBCL亚型中（<2%），但在MZL中相对常见（8%）。事实上，BCL 10对MZ B细胞至关重要， 发展和其过度表达介导过度增殖和最终MZ起源的淋巴瘤。 然而，BCL 10突变对淋巴瘤发生的影响尚未研究。 BCL 10与CARD 11和MALT 1形成高级复合物（CBM），也是淋巴瘤癌基因。这个复杂 作为一个对接平台，用于募集和激活其他蛋白质，导致NF-κB激活。BCL10 DLBCL中的体细胞突变可分为：CARD结构域错义突变体和C-末端截短突变体。 BCL 10 CARD介导CARD 11-BCL 10和BCL 10-BCL 10相互作用，而BCL 10 C-末端结构域 介导BCL 10-MALT 1相互作用。在初步研究中，这两类突变体都加速了BCL 10的表达。 聚合，重新连接复合物结构和组成，并诱导NF-κB介导的组成性激活 转录和MALT 1蛋白酶活性。 我们假设CARD和C末端突变诱导功能获得性，并通过以下途径驱动淋巴瘤发生： 激活CBM复合物活性及其下游信号通路，包括NF-κB， 通过不同的分子机制。根据我们的初步结果，我们预测：i）BCL 10的增益- 功能突变将通过破坏BCL 10的自抑制结构来增强CBM复合物的活性， 基于CARD错义或C末端截短的特定生化效应的不同分子机制 突变; ii）这将导致与NOTHC 2激活突变协同的淋巴瘤发生的加速， 和iii）BCL 10功能获得性突变将赋予对经典BCR途径激酶抑制剂的抗性， 作为伊布替尼（BTK抑制剂），因此需要靶向下游蛋白，如MALT 1抑制剂或替代物 途径。 我们的目标是阐明特定BCL 10体细胞突变的分子机制， 类改变CBM复合物的高级分子结构，以确定这如何影响MZ B细胞 生长和存活导致淋巴瘤，并利用这些信息来设计新的治疗方法， C1/BN 2淋巴瘤。

Role of BCL10 somatic mutations in lymphomagenesis and response to BCR-targeted therapies ABSTRACT Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy and a molecularly heterogenous disease. Two recent genomic profiling studies of large DLBCL patient series subclassified these patients in five distinct genomic groups. Both studies essentially agreed in their classification and described a previously unnoticed subtype reminiscent of Marginal Zone Lymphoma (MZL), namely C1 or BN2 lymphoma. This C1/BN2 subtype is characterized by frequent translocations of BCL6 and activating mutations of NOTCH2 and NF-κB signaling genes. Among the latter, 30% of the patients displayed BCL10 mutations, which are rare in other DLBCL subtypes (<2%) but relatively common in MZL (8%). In fact, BCL10 is critical for MZ B-cell development and its overexpression mediates hyperproliferation and eventually lymphomas of MZ origin. However, the effect of BCL10 mutations on lymphomagenesis has not been studied. BCL10 forms a high order complex (CBM) with CARD11 and MALT1, also lymphoma oncogenes. This complex serves as a docking platform for recruitment and activation of other proteins leading to NF-κB activation. BCL10 somatic mutations in DLBCL can be classified in: CARD domain missense and C-terminus truncating mutants. BCL10 CARD mediates CARD11-BCL10 and BCL10-BCL10 interactions while BCL10 C-terminal domain mediates BCL10-MALT1 interaction. In preliminary studies, both classes of mutants accelerate BCL10 polymerization, rewire complex structure and composition and, induce constitutive activation of NF-κB mediated transcription and MALT1 protease activity. We hypothesize that CARD and C-terminal mutations induce gain-of-function and drive lymphomagenesis by activating CBM complex activity and its downstream signaling pathways including NF-κB and that they will do so through distinct molecular mechanisms. Based in our preliminary results, we predict that: i) BCL10 gain-of- function mutations will enhance CBM complex activity by disrupting BCL10 auto-inhibitory structure through distinct molecular mechanisms based on specific biochemical effects of CARD missense or C-terminal truncating mutations; ii) this will cause acceleration of lymphomagenesis in cooperation with NOTHC2 activating mutations, and iii) BCL10 gain-of-function mutations will confer resistance to classical BCR pathway kinase inhibitors such as Ibrutinib (BTK inhibitor), thus requiring targeting downstream proteins such as MALT1 inhibitors or alternative pathways. Our goals for this proposal are to elucidate the molecular mechanism by which specific BCL10 somatic mutations classes alter the high order molecular structure of the CBM complex, to determine how this impacts MZ B-cell growth and survival to cause lymphomas, and to leverage this information to design of novel therapeutic approaches for C1/BN2 lymphomas.