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

Bcl10基因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，是一种 异质性疾病。最近对大型DLBCL患者系列的两项基因组图谱研究将这些患者细分为 五个不同基因组组的患者。这两项研究在分类上基本一致，并描述了一种 以前未被注意到的亚型使人想起边缘地带淋巴瘤(MZL)，即C1型或BN2型。 这种C1/BN2亚型的特征是BCL6的频繁易位和NOTCH2的激活突变 和核因子-κB信号转导基因。在后者中，30%的患者表现出罕见的bcl10突变。 在其他DLBCL亚型中(&lt；2%)，但在MZL中相对常见(8%)。事实上，Bcl10对MZ B细胞至关重要 发育及其过度表达介导了过度增殖，并最终导致了起源于MZ的淋巴瘤。 然而，Bcl10突变对淋巴肿大的影响还没有研究。 Bcl10与CARD11和MALT1形成高阶复合体(CBM)，也是淋巴瘤癌基因。这个建筑群 作为一个对接平台，招募和激活导致NF-κB激活的其他蛋白质。BCL10 DLBCL的体细胞突变可分为：CARD结构域错义突变和C末端截断突变。 Bcl10卡介导CARD11-Bcl10和Bcl10-Bcl10的相互作用，而Bcl10C-末端结构域 介导Bcl10-MALT1相互作用。在初步研究中，这两类突变体都加速了Bcl10 聚合，重组复合体结构和组成，并诱导NF-κB介导的构造性激活 转录和MALT1蛋白酶活性。 我们假设CARD和C-末端突变通过以下途径诱导功能获得并驱动淋巴肿大 激活煤层气复合体活性及其下游信号通路，包括核因子-κB，它们将发挥作用 所以通过不同的分子机制。根据我们的初步结果，我们预测：i)BCL10-增益- 功能突变通过破坏Bcl10自身抑制结构增强煤层气复合体活性 基于CARD错义或C末端截断的特定生化效应的不同分子机制 突变；ii)这将与NOTHC2激活突变协同导致淋巴肿大的加速， 和iii)bcl10功能获得突变将使人对经典的bcr途径激酶抑制剂产生耐药性，如 作为伊布鲁替尼(BTK抑制剂)，因此需要靶向下游蛋白，如MALT1抑制剂或替代 小路。 我们这个提议的目标是阐明特定的bcl10体细胞突变的分子机制。 类改变了CBM复合体的高阶分子结构，以确定这如何影响MZ B细胞 导致淋巴瘤的生长和存活，并利用这一信息设计新的治疗方法 C1/BN2型淋巴瘤的手术入路。

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.