BAF complex deregulation in lymphoma

淋巴瘤中 BAF 复合物失调

基本信息

批准号：
10675768
负责人：
Michael Richard Green
金额：
$ 67.24万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-02 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10675768
关键词：
ARID1A gene Adopted Affect Alleles Animals Automobile Driving B cell differentiation B lymphoid malignancy B-Cell Development B-Cell Lymphomas B-Lymphocytes Binding Sites Biology Bladder Burkitt Lymphoma Catalytic Domain Cell Communication Cell Line Cells Characteristics Chromatin Chromatin Remodeling Factor Complex Darkness Dependence Disease Disease Progression Enhancers Epigenetic Process Etiology Failure Family Frequencies Future Gene Activation Gene Expression Gene Expression Regulation Genes Genetic Genetic Transcription Genomic approach Genomics Histologic Human Immunologics Knockout Mice Lead Light Lymphoma Lymphomagenesis Malignant - descriptor Malignant Neoplasms Maps Modeling Molecular Molecular Analysis Mutation Nucleosomes Organoids Outcome Patient-Focused Outcomes Patients Pattern Phenotype Play Process Progression-Free Survivals Public Health RELA gene Reaction Recurrence Refractory Regulatory Element Role SMARCA4 gene SPI1 gene Signal Transduction Somatic Mutation Stomach Structure of germinal center of lymph node T-Lymphocyte TNFRSF5 gene Therapeutic Toxic effect Transcriptional Activation Tumor Suppressor Genes Tumor Suppressor Proteins Uterus Work chemotherapy chromatin remodeling cohort conditional knockout driver mutation epigenetic regulation immunological synapse immunological synapse formation improved outcome insight large cell Diffuse non-Hodgkin&apos s lymphoma loss of function mortality overexpression patient derived xenograft model precision medicine prevent programs promoter protein expression response rituximab standard care targeted treatment tositumomab transcription factor transcriptome sequencing tumor tumor-immune system interactions

项目摘要

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.

项目概要伯基特淋巴瘤 (BL) 和弥漫性大 B 细胞淋巴瘤 (DLBCL) 是高度侵袭性的 B 细胞恶性肿瘤通常采用化疗加抗 CD20 抗体高强度利妥昔单抗治疗。 BL 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% 能够忍受治疗的患者中，36% 的患者会出现疾病进展并出现令人沮丧的情况。原发难治性患者的 3 年无进展生存率仅为 1%。的 DLBCL 患者在一线治疗期间/之后出现进展，中位总生存期为 6.3 个月。最近的基因组研究发现，在 BL 和然而，尚未对这些驱动因素进行详细的功能分析。突变，因此目前这两种疾病都没有可用的靶向治疗策略。 SMARCA4 和 ARID1A 基因突变同时存在于大约 40% 的 BL 肿瘤中，12% 的 BL 肿瘤中同时存在。这些基因编码多亚基复合物 BAF（又名 SWI/SNF）的两个组成部分。复合体，其功能是通过“解包”封闭和沉默状态使其变为开放来激活基因表达 SMARCA4 的突变通过影响催化结构域来扰乱其活性，并且 SMARCA4 的突变会影响其活性。 ARID1A 导致蛋白质表达丧失，共同代表了功能丧失的两种替代机制尽管最近在其他文献中描述了 BAF 复合体的功能。恶性肿瘤、其在 B 细胞发育过程中的功能，以及其在 B 细胞中失活的结果淋巴瘤，仍有待探讨。我们开发了 SMARCA4 和 ARID1A 失活的动物和细胞系模型，并发现它们我们将利用这些模型和尖端基因组学来调节 B 细胞发育的不同过程。了解 BAF 复合物失调的分子和免疫学后果的方法通过对比和比较 BAF 复合物的两个关键成分的作用， SMARCA4 和 ARID1A，我们希望详细了解离散 BAF 复合物的作用及其这项工作将揭示携带 BAF 的 BL 和 DLBCL 肿瘤的生物学特性。复杂的突变，可以导致这种疾病的精准医学靶向和治疗的进步，以及其他癌症。