Overcoming Drug Resistance Driven by BCL10 Mutations in Diffuse Large B Cell Lymphoma

项目摘要 弥漫性大B细胞淋巴瘤（DLBCL）是一种侵袭性非霍奇金淋巴瘤， 恶性血液病DLBCL表现出显著的分子和临床异质性，但所有患者均为 用标准的化学免疫疗法治疗因此，临床上强烈需要鉴定以下生物标志物： 药物反应和新疗法，以改善患者的结果。BCL 10突变在DLBCL中普遍存在 亚型和复发突变经常截短BCL 10蛋白的调节C末端。BCL 10是一种 CARD 11（CARMA 1）-BCL 10-MALT 1复合物的核心组分，其激活下游致癌基因 DLBCL中的JNK和NF-kB等通路;然而，BCL 10突变促进DLBCL的机制 DLBCL中的淋巴瘤发生知之甚少。最近的结果暗示BCL 10突变在诱导 NF-kB信号传导和MALT 1蛋白酶活性以及布鲁顿酪氨酸激酶抑制剂（BTKi）抗性。的 总体目标是了解BCL 10突变在DLBCL中的作用，以确定药物治疗的机制， 耐药性，并确定这些突变患者的替代治疗策略。中央 假设BCL 10突变在本质上是激活的，驱动淋巴瘤发生和对BTKis的抗性， 将通过以下具体目标进行测试：1）了解BCL 10突变在 使用遗传准确的体内模型的淋巴瘤发生，和2）确定替代治疗 靶向克服由BCL 10突变介导的耐药性。目标1将描述生存率， 在实验室中产生的含有诱导型BCL 10截短突变的新型小鼠模型的肿瘤发生率 在C57 BL/6 J小鼠的ROSA 26基因座上表达。该模型通过B细胞特异性的 使用Cre-重组激活BCL 10突变，并且还将与过表达BCL 6的小鼠杂交， 这发生在BCL 10突变的背景下。目标2将确定攻击BCL 10突变细胞的化合物 通过实施靶向BCR、NF-κ B和BTK的小分子协同筛选， kB和平行信号通路。预期的结果是建立遗传准确的体内模型 BCL 10突变，以了解其淋巴瘤发生的潜力，将BCL 10定义为BTKi的生物标志物 耐药性，并确定新的，有针对性的依赖性诱导BCL 10突变。拟议研究 它将揭示淋巴瘤发生的机制，识别生物标志物以指导临床 DLBCL的决策，并发现潜在的药物靶点，以克服耐药性或与现有的 治疗此外，这些研究是创新的，因为所描述的小鼠模型将是第一个表征 BCL 10基因在体内的突变，将为研究淋巴瘤的发生和耐药性驱动提供一个新的背景 BCL 10突变总的来说，这项研究将产生积极的影响，因为确定BCL 10作为生物标志物， 对治疗的反应和确定BCL 10突变患者的治疗策略将指导 治疗选择和改善DLBCL患者的结局。

Project Summary Diffuse large B cell lymphoma (DLBCL) is an aggressive non-Hodgkin lymphoma and the most common hematologic malignancy. DLBCL exhibits significant molecular and clinical heterogeneity, yet all patients are treated with standard chemoimmunotherapy. As such, there is a strong clinical need to identify biomarkers of drug response and novel therapies to improve patient outcomes. BCL10 mutations are prevalent among DLBCL subtypes and recurrent mutations frequently truncate the BCL10 protein’s regulatory C-terminus. BCL10 is a core component of the CARD11 (CARMA1)-BCL10-MALT1 complex, which activates downstream oncogenic pathways like JNK and NF-kB in DLBCL; however, the mechanisms by which BCL10 mutations promote lymphomagenesis in DLBCL are poorly understood. Recent results implicate BCL10 mutations in the induction of NF-kB signaling and MALT1 protease activity and Bruton’s Tyrosine Kinase inhibitor (BTKi) resistance. The overall objective is to understand the role of BCL10 mutations in DLBCL, to determine mechanisms of drug resistance and to identify alternative treatment strategies for patients with these mutations. The central hypothesis that BCL10 mutations are activating in nature, driving lymphomagenesis and resistance to BTKis, will be tested through the following specific aims: 1) Understand the role of BCL10 mutations in lymphomagenesis using genetically accurate in vivo models, and 2) Identify alternative therapeutic targets to overcome drug resistance mediated by BCL10 mutations. Aim 1 will characterize survival and tumor incidence of a novel murine model generated in the lab containing an inducible BCL10 truncation mutation expressed on the ROSA26 locus of C57BL/6J mice. The model mimics human disease through B-cell-specific activation of BCL10 mutations using Cre-recombination and will also be crossed with mice overexpressing BCL6, which occurs in context with BCL10 mutations. Aim 2 will identify compounds to attack BCL10 mutated cells alone or in combination with BTKis by implementing small molecule synergy screens that target the BCR, NF- kB and parallel signaling pathways. The expected outcome is the creation of genetically accurate in vivo models of BCL10 mutations to understand their lymphomagenic potential, to define BCL10 as a biomarker of BTKi resistance, and to identify novel, targetable dependencies induced by BCL10 mutations. The proposed research is significant because it will uncover mechanisms of lymphomagenesis, identify biomarkers to guide clinical decision-making in DLBCL and discover potential drug targets to overcome resistance or synergize with existing therapies. Also, these studies are innovative because the described mouse model will be the first to characterize BCL10 mutations in vivo and will provide a novel context to study lymphomagenesis and drug resistance driven by BCL10 mutations. Overall, this research will have positive impacts as identifying BCL10 as a biomarker for response to therapy and determining a therapeutic strategy for patients with BCL10 mutations will guide treatment options and improve outcomes in DLBCL patients.