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.

研究摘要非霍奇金淋巴瘤是美国癌症的第五个主要原因。其中，散射大 B细胞淋巴瘤（DLBCL）和Follic淋巴瘤（FL）代表两种最常见的形式，一起占诊断的60％以上。尽管在治疗这些疾病方面取得了显着进步，但多达40％的DLBCL患者的死亡率仍然很高，FL虽然被认为是一种懒惰的疾病，但是在高级阶段无法治愈，通常会变成高度侵略性的恶性肿瘤。复发和转化与维持“创始人”突变子集的常见突变祖细胞有关存在于诊断性肿瘤克隆中。因此，对共同的生物学的了解得到了改善前体和可能容易受到靶向治疗干预措施的机制的识别是因此，为了提高我们治愈这些疾病的能力的优先事项。使CREBBP乙酰转移酶失活的体突变，包括截断和帽子域错义突变是FL的第二大常见遗传改变（占病例的70％）和DLBCL （属于最近确定的EZB/C3遗传子集的40％的病例），揭示了对 GC衍生淋巴瘤发病机理中的表观遗传畸变（Pasqualucci等，Nature，2011; Morin et eT Al。，Nature 2011）。 CREBBP突变代表肿瘤系统发育进化过程中的早期事件，在获得额外的致癌病变之前，由普通突变前体获得（Pasqualucci）等，Cell Reports 2014； Okosun等人，自然遗传学2014）。确实，降低剂量的CREBBP协同作用通过BCL2放松管制，可以增强类似人类的FL/DLBCL的发展。截断突变有是广泛研究的，错义突变的作用在很大程度上仍然是出乎意料的。这是一个很大的差距在考虑这种错义突变是FL的绝大多数Crebbb改变时，这些等位基因与截断突变不同，表明它们可能会干扰具有其他乙酰基转移酶或转录复合物的补偿机制。在与此假设相符，我们和其他人的初步数据表明，热点Crebbp错过与在CREBBP缺陷型细胞中观察到的相比，HAT突变会引起明显的变化。在这些结果的基础上，该项目的一般目标是阐明Crebbp错过的影响（vs截断）在体内对前体GC B细胞的恶性转化的突变，三个特定目的：i）研究最常见的R1446H突变宿主点在GC响应中的体内作用淋巴作用； ii）确定由错义与 GC B细胞前体中的截断突变； iii）研究CREBBP突变在重编程中的作用 GC微环境。我们预计从这些研究获得的结果将提供新的见解关于机制引发了肿瘤转化及其特定的治疗靶向。