BAF complex deregulation in lymphoma

项目总结 Burkitt淋巴瘤(BL)和弥漫性大B细胞淋巴瘤(DLBCL)是高度侵袭性B细胞恶性肿瘤 通常采用化疗加抗CD20抗体利妥昔单抗治疗。高强度 白血病患者需要化疗，这与严重的毒性和治疗相关的死亡率有关 在10%的患者中。在能够忍受治疗的患者中，36%的患者会出现病情恶化和情绪低落 结果，在原发难治的患者中，只有1%的3年无进展生存率。相似的分数 大多数DLBCL患者在一线治疗期间/之后进展，中位总生存期为6.3个月。 最近的基因组研究已经发现了高度复发的同现基因改变。 DLBCL肿瘤。然而，还没有对这些驱动程序中的大多数进行详细的功能分析 突变，因此目前对这两种疾病都没有可用的靶向治疗策略。 SMARCA4和ARID1A基因突变在大约40%的淋巴瘤和12%的淋巴瘤中被发现。 DLBCL肿瘤。这些基因编码多亚单位复合体的两个组成部分，即BAF(又名SWI/SNF)。 复合体，其功能是通过将封闭和沉默状态解包为开放状态来激活基因表达 和活跃的基因。SMARCA4的突变通过影响催化结构域而扰乱其活性，而SMARCA4的突变 ARID1A导致蛋白质表达丧失，共同代表了两种可供选择的功能丧失机制 在BAF建筑群里。尽管最近在其他文献中描述了BAF复合体的功能 恶性肿瘤及其在B细胞发育过程中的功能，因此其在B细胞中失活的后果 淋巴瘤，仍有待探索。 我们已经建立了SMARCA4和ARID1A失活的动物和细胞系模型，并发现它们 调节B细胞发育的不同过程。我们将利用这些模型和尖端基因组学 了解BAF复合体解除调控的分子和免疫学后果的方法 在B细胞淋巴瘤中。通过对比和比较BAF复合体的两个关键组件的作用， SMARCA4和ARID1A，我们希望详细了解离散BAF复合体的作用及其 冗余和非冗余角色。这项工作将揭示携带BAF的BL和DLBCL肿瘤的生物学 复杂的突变，这可能导致精准医学靶向和这种疾病的治疗方法的进步， 对于其他癌症也是如此。

PROJECT SUMMARY Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL) are highly aggressive B-cell malignancies that are commonly treated with chemotherapy plus an anti-CD20 antibody, Rituximab. High-intensity chemotherapy is required in BL patients, which is associated with severe toxicity and treatment-related mortality in 10% of patients. Of the patients able to endure therapy, 36% will suffer disease progression and have a dismal outcome, with only a 1% 3-year progression-free-survival in patients that are primary-refractory. A similar fraction of DLBCL patients progress during/following first-line therapy and have a median overall survival of 6.3 months. Recent genomic studies have identified co-occurring genetic alterations that are highly-recurrent in BL and DLBCL tumors. However, detailed functional analyses have not been performed for the majority of these driver mutations, and hence there are currently no available targeted therapeutic strategies in either disease. Mutations of the SMARCA4 and ARID1A genes are together found in approximately 40% of BL tumors, and 12% of DLBCL tumors. These genes encode two components of a multi-subunit complex, the BAF (aka SWI/SNF) complex, which functions to activate gene expression by “unpacking” closed and silent states to become open and active genes. Mutations of SMARCA4 perturb its activity by affecting the catalytic domain, and mutations of ARID1A lead to loss of protein expression, together representing two alternative mechanisms for loss of function in the BAF complex. Although the function of the BAF complex has been recently described in other malignancies, its function during B-cell development, and therefore the consequence of its inactivation in B-cell lymphoma, remains to be explored. We have developed animal and cell line models of SMARCA4 and ARID1A inactivation and found that they regulate distinct processes in B-cell development. We will leverage these models and cutting-edge genomics approaches to understand both the molecular and immunological consequences of BAF complex deregulation in B-cell lymphoma. By contrasting and comparing the roles of two key components of the BAF complex, SMARCA4 and ARID1A, we hope to gain detailed insight into the role of discrete BAF complexes and their redundant and non-redundant roles. This work will uncover the biology of BL and DLBCL tumors carrying BAF complex mutations, which can lead to advances in precision medicine targeting and therapies for this disease, as well as for other cancers.