Role of CREBBP missense mutations in lymphomagenesis

CREBBP错义突变在淋巴瘤发生中的作用

基本信息

批准号：
10367483
负责人：
Laura Pasqualucci
金额：
$ 47.51万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
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：
2022-01-01 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10367483
关键词：
ATAC-seq Accounting Acetyltransferase Affect Alleles Antigen Presentation Pathway Antigen-Presenting Cells B-Cell Antigen Receptor B-Cell Lymphomas B-Lymphocytes BCL2 gene Biological Assay Biological Markers Biology CREBBP gene Cancer Etiology Cells ChIP-seq Chromatin Clinical Complex Coupled DNA Sequence Alteration Data Dependence Development Diagnosis Diagnostic Disease Disease remission Enhancers Epigenetic Process Event Evolution Fluorescence Microscopy Follicular Lymphoma Frequencies Gene Expression Profile Genetic Genetic Transcription Goals Human Incidence Indolent Induced Mutation Inferior Knock-in Mouse Knock-out Knockout Mice Lesion Link Lymphoma Lymphomagenesis Maintenance Malignant - descriptor Malignant Neoplasms Malignant lymphoid neoplasm Mediating Memory B-Lymphocyte Missense Mutation Modeling Modification Molecular Mouse Strains Mus Mutate Mutation Nature Neoplastic Cell Transformation Non-Hodgkin&apos s Lymphoma Non-Malignant Oncogenic Outcome Outcome Study Pathogenesis Patients Pattern Phenotype Phylogenetic Analysis Plasma Cells Proteins RNA Decay Recurrence Relapse Reporting Research Research Proposals Role Sampling Signal Transduction Somatic Mutation Structure Structure of germinal center of lymph node TNFRSF5 gene Therapeutic Therapeutic Intervention Tumor Suppressor Proteins United States Validation Work base conventional therapy dosage founder mutation improved in vivo insight large cell Diffuse non-Hodgkin&apos s lymphoma mass spectrometric imaging mortality mouse model mutant neoplastic novel therapeutic intervention patient population precursor cell programs protein expression recruit response single cell analysis single-cell RNA sequencing stem cells targeted treatment therapeutic target transcriptome sequencing tumor tumor-immune system interactions

项目摘要

RESEARCH SUMMARY Non-Hodgkin lymphomas are the 5th leading cause of cancer in the United States. Among them, diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) represent the two most common forms, together accounting for over 60% of diagnoses. Despite remarkable advances in the treatment of these diseases, mortality remains high in as many as 40% of DLBCL patients, and FL, although regarded as an indolent disease, is incurable in advanced stages, often transforming into a highly aggressive malignancy. Relapse and transformation are linked to common mutated progenitor cells that maintain a subset of “founder” mutations present in the diagnostic dominant tumor clone. Therefore, improved understanding of the biology of the common precursor and the identification of mechanisms that could be vulnerable to targeted therapeutic intervention are therefore a priority in order to advance our ability to cure these diseases. Somatic mutations that inactivate the CREBBP acetyltransferase, including truncating and HAT domain missense mutations, emerged as the second most common genetic alteration in FL (70% of cases) and DLBCL (40% of cases belonging to the recently identified EZB/C3 genetic subset), revealing a prominent role for epigenetic aberrations in the pathogenesis of GC-derived lymphomas (Pasqualucci et al., Nature 2011; Morin et al., Nature 2011). CREBBP mutations represent early events during the tumor phylogenetic evolution, which are acquired by the common mutated precursor prior to the acquisition of additional oncogenic lesions (Pasqualucci et al, Cell Reports 2014; Okosun et al., Nature Genetics 2014). Indeed, reduced dosage of CREBBP synergizes with BCL2 deregulation to enhance the development of human-like FL/DLBCL. While truncating mutations have been extensively studied, the role of missense mutations remains largely unexplored. This is a significant gap when considering that missense mutations account for the overwhelming majority of CREBBP alterations in FL, and that different from truncating mutations, these alleles are expressed, suggesting that they could interfere with compensatory mechanisms by other acetyltransferases or the recruitment of transcription complexes. In line with this hypothesis, preliminary data from us and others have shown that the hotspot CREBBP missense HAT mutation induces distinct changes compared to those observed in CREBBP-deficient cells. Building on these results, the general goal of this project is to elucidate the impact of CREBBP missense (vs truncating) mutations on the malignant transformation of the precursor GC B cell in vivo, with three Specific Aims: i) investigate the in vivo role of the most common R1446H mutational hostspot in GC responses and lymphomagenesis; ii) identify the shared vs unique transcriptional programs dysregulated by missense vs truncating mutations in the GC B cell precursor; iii) investigate the role of CREBBP mutations in reprogramming the GC microenvironment. We anticipate that the results obtained from these studies will provide new insights on the mechanisms initiating neoplastic transformation and on their specific therapeutic targeting.

研究概要非霍奇金淋巴瘤是美国第五大癌症，其中弥漫性大。 B 细胞淋巴瘤 (DLBCL) 和滤泡性淋巴瘤 (FL) 代表两种最常见的形式尽管这些疾病的治疗取得了显着进展，但占诊断的 60% 以上。 DLBCL 患者的死亡率仍然很高，高达 40%，而 FL 尽管被认为是一种惰性疾病，在晚期阶段是无法治愈的，通常会转变为高度侵袭性的恶性肿瘤。转化与维持“创始人”突变子集的常见突变祖细胞有关存在于诊断显性肿瘤克隆中，因此提高了对常见生物学的了解。前体和识别可能容易受到针对性治疗干预的机制是因此，提高我们治愈这些疾病的能力是当务之急。使 CREBBP 乙酰转移酶失活的体细胞突变，包括截短和 HAT 结构域错义突变，成为 FL（70% 病例）和 DLBCL 中第二常见的基因改变（40% 的病例属于最近发现的 EZB/C3 遗传子集），揭示了 GC 衍生淋巴瘤发病机制中的表观遗传畸变（Pasqualucci 等人，Nature 2011；Morin 等人，2011 年） al.，Nature 2011）。CREBBP 突变代表肿瘤系统发育过程中的早期事件，即在获得额外的致癌病变之前，由常见突变前体获得（Pasqualucci 等人，Cell Reports 2014；Okosun 等人，Nature Genetics 2014）确实，减少 CREBBP 剂量具有协同作用。 BCL2 失调可促进类人 FL/DLBCL 的发展，而截短突变则有。尽管已经进行了广泛的研究，但错义突变的作用在很大程度上仍未得到探索，这是一个重大差距。当考虑到错义突变占 FL 中 CREBBP 改变的绝大多数时，与截短突变不同的是，这些等位基因是表达的，这表明它们可能会干扰具有其他乙酰转移酶或转录复合物募集的补偿机制。与这一假设相符，我们和其他人的初步数据表明，热点 CREBBP 错义与 CREBBP 缺陷细胞中观察到的变化相比，HAT 突变引起明显的变化。基于这些结果，该项目的总体目标是阐明 CREBBP 错义的影响（与截短）突变对前体 GC B 细胞体内恶性转化的影响，具有三种特异性目的： i) 研究最常见的 R1446H 突变宿主点在 GC 反应中的体内作用和淋巴瘤发生；ii) 识别错义与独特转录程序的失调截断 GC B 细胞前体中的突变；iii) 研究 CREBBP 突变在重编程中的作用我们预计从这些研究中获得的结果将提供新的见解。关于启动肿瘤转化的机制及其具体的治疗目标。