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.

项目摘要 Burkitt淋巴瘤（BL）和弥漫性大B细胞淋巴瘤（DLBCL）是高度侵略性的B细胞Malignancys 通常用化学疗法和抗CD20抗体利妥昔单抗治疗。高强度 BL患者需要化学疗法，这与严重毒性和与治疗相关的死亡率有关 10％的患者。患者可以忍受治疗，36％将遭受疾病的进展，并有沮丧结果，初次难治性的患者中只有1％3年的无进展生存。类似的部分在一线治疗期间/之后，DLBCL患者的进展，中位总生存期为6.3个月。最近的基因组研究已经确定了在BL和BL和 DLBCL肿瘤。但是，尚未针对大多数这些驱动程序进行详细的功能分析突变，因此目前在任何一种疾病中都没有可用的靶向治疗策略。在大约40％的BL肿瘤中发现了SMARCA4和ARID1A基因的突变，而12％ DLBCL肿瘤。这些基因编码了多支化合物复合物的两个组成部分，即BAF（又称SWI/SNF）复杂的复合物，可以通过“解开”封闭和沉默的状态来激活基因表达的功能和活性基因。 Smarca4的突变通过影响催化域和突变来扰动其活性 ARID1A导致蛋白质表达的丧失，共同代表了功能丧失的两个替代机制在BAF复合体中。尽管最近在其他中描述了BAF复合物的功能 Malignancys，其在B细胞开发过程中的功能，因此其在B细胞中失活的结果淋巴瘤仍有待探索。我们已经开发了Smarca4和Arid1a灭活的动物和细胞系模型，发现它们调节B细胞开发中的不同过程。我们将利用这些模型和尖端的基因组学了解BAF复合物放松管制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复合物的两个关键组成部分的作用， Smarca4和Arid1a，我们希望能够详细了解离散BAF复合物及其的作用冗余和非冗余角色。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，这可能会导致对这种疾病的精确医学靶向和疗法的进步以及其他癌症。