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

BCL10 体细胞突变在淋巴瘤发生和 BCR 靶向治疗反应中的作用

• 批准号: 10174888
• 负责人: Leandro C Cerchietti
• 金额: $ 55.71万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10174888
• 关键词: Acceleration; Affect; Antigens; Automobile Driving; B-Cell Activation; B-Cell Antigen Receptor; B-Cell Development; B-Cell NonHodgkins Lymphoma; B-Lymphocytes; BCL1 Oncogene; BCL10 gene; BCL2 gene; BCL6 gene; BCR Signaling Pathway; Binding; Biochemical; Biological; Biology; Bypass; C-terminal; Categories; Cell Line; Cell Survival; Classification; Clinic; Complex; Crystallization; Data; Development; Disease; Docking; Drug Targeting; Gene Expression Profile; Gene Expression Profiling; Genes; Genetic; Genetic Transcription; Genomics; Goals; Higher Order Chromatin Structure; In Vitro; Induced Mutation; Knowledge; Lymphoma; Lymphomagenesis; Malignant - descriptor; Malignant lymphoid neoplasm; Mediating; Missense Mutation; Molecular; Molecular Structure; Mucosa- associated lymphoid tissue lymphoma translocation protein-1; Mutation; NF-kappa B; Oncogenes; Pathway interactions; Patients; Peptide Hydrolases; Proteins; Proto-Oncogenes; Regimen; Resistance; Rest; Role; Series; Set protein; Signal Pathway; Signal Transduction; Somatic Mutation; Structure; Therapeutic; Toll-like receptors; base; cell growth; design; gain of function; gain of function mutation; genetic profiling; improved; in vivo; inhibitor/antagonist; kinase inhibitor; large cell Diffuse non-Hodgkin' s lymphoma; molecular subtypes; mutant; novel; novel therapeutic intervention; overexpression; p65; polymerization; precision medicine; preclinical development; recruit; response; targeted treatment; treatment strategy; tumor

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.

Bcl10体突变在淋巴作用和对BCR靶向疗法的反应中的作用 抽象的 弥漫性大B细胞淋巴瘤（DLBCL）是最常见的淋巴性恶性肿瘤，是分子 异质疾病。大型DLBCL患者系列的两项最近的基因组分析研究将这些研究列为分类 五个不同基因组组的患者。两项研究本质上都在分类中达成了一致，并描述了 以前未注明的亚型让人联想到边缘区淋巴瘤（MZL），即C1或BN2淋巴瘤。 该C1/BN2亚型的特征是经常易位Bcl6和激活Notch2的突变 和NF-κB信号转导基因。在后者中，有30％的患者显示出Bcl10突变，这是罕见的 在其他DLBCL亚型中（<2％），但在MZL中相对常见（8％）。实际上，BCL10对于MZ B细胞至关重要 发育及其过表达介导了MZ起源的高增殖和最终的淋巴瘤。 然而，BCl10突变对淋巴细胞的影响尚未研究。 Bcl10与Card11和Malt1（淋巴瘤癌基因）形成高级复合物（CBM）。这个复合物 作为导致NF-κB激活的其他蛋白质募集和激活的对接平台。 BCl10 DLBCL中的体细胞突变可以分类为：卡域错过和C末端截断突变体。 Bcl10卡介导Card11-BCl10和Bcl10-BCl10相互作用，而Bcl10 C末端域 介导Bcl10-MALT1相互作用。在初步研究中，两类突变体加速了Bcl10 聚合，重新复合结构和组成，并诱导NF-κB介导的本构激活 转录和MALT1蛋白酶活性。 我们假设该卡和C末端突变会诱导功能获得，并通过 激活CBM复合活动及其下游信号通路，包括NF-κB，他们将做 因此，通过不同的分子机制。基于我们的初步结果，我们预测：i）Bcl10- 功能突变将通过通过破坏Bcl10自动抑制性结构来增强CBM复合活动 基于卡错义或C末端截断的特定生化效应的不同分子机制 突变； ii）这将在与NotHC2激活突变合作时导致淋巴作用加速， iii）Bcl10功能获得突变将赋予经典BCR途径激酶抑制剂的抗性此类 如ibrutinib（BTK抑制剂），因此需要靶向下游蛋白，例如MALT1抑制剂或替代方案 途径。 该提案的目标是阐明特定Bcl10体细胞突变的分子机制 类改变CBM复合物的高阶分子结构，以确定这如何影响MZ B细胞 生长和生存引起淋巴瘤，并利用这些信息来设计新型治疗。 C1/BN2淋巴瘤的方法。