权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Cooperation of SF3B1 mutations and ATM deletions in the pathogenesis of chronic lymphocytic leukemia

SF3B1突变和ATM缺失在慢性淋巴细胞白血病发病机制中的协同作用

基本信息

批准号：
10376233
负责人：
Lili Wang
金额：
$ 42.38万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10376233
关键词：
11q ATM Gene Mutation Acceleration Alternative Splicing B-Lymphocytes Biology Blood CD19 gene CRISPR/Cas technology Cell Aging Cell Cycle Regulation Cells Chromosomal Instability Chromosomes Chronic Lymphocytic Leukemia Clinic Clinical Trials Clonal Evolution Clonal Expansion DNA DNA Damage DNA Repair DNA damage checkpoint DNA sequencing Data Dependence Development Disease Progression Excision Foundations Frequencies Genes Genetic Genomic Instability Genotype Goals Hybrids Impairment Introns Knowledge Lesion Link Literature Location Malignant - descriptor Marrow Mitotic Modeling Molecular Mus Mutate Mutation North America PTPRC gene Pathogenesis Pathway interactions Patients Pattern Penetrance Phenotype Publishing RNA RNA Splicing Recurrence Research Sampling Signal Pathway Signal Transduction Site Somatic Mutation Spleen Stress Structure Testing Variant Work Yin adult leukemia aged aurora B kinase base cancer cell chemotherapy chronic lymphocytic leukemia cell cytotoxicity design early onset genetic information genome-wide in vivo inhibitor loss of function mouse model mutant novel peripheral blood replication stress response treatment response tumorigenesis whole genome

项目摘要

Project Summary World-wide sequencing efforts have identified recurrent novel genetic lesions associated with disease progression, inferred patterns of common co-occurrence, and characterized clonal evolution in response to treatments in chronic lymphocytic leukemia. Despite the wealth of available genetic information, these analyses all rely on statistical inference, thus limiting the possibility to link the genotype to the phenotype. Currently, understanding functions of high frequency genetic lesions and how they cooperate with their co-occurring mutations to cause CLL initiation and progression are not available. In this proposal, we aim to understand how two of the most recurrent genetic lesions in CLL (SF3B1 mutations and ATM deletions) mechanistically impact CLL initiation and progression with the overarching goal to understand CLL biology, generate novel murine model, and find new strategies for treating CLL with these lesions. This proposal is based on our finding that co-expression of mutated Sf3b1 with Atm deletion resulted in the development of clonal pathognomonic CD19+CD5+ B cells in blood, marrow and spleen at low penetrance in aged (18 months) mice, that can be propagated by in vivo passaging. Interestingly, whole-genome sequencing of DNA from murine CLL revealed recurrent chromosome amplifications, suggesting chromosome instability as a mechanism contributing to CLL in the mice with Sf3b1 mutation and Atm deletion. We now propose to investigate the hypothesis that SF3B1 mutations promote genomic instability through RNA splicing related R- loop formation while ATM deletion further augment genomic instability through decreasing R-loop associated DNA damage repair (Aim 1). We further hypothesize that modulation of the R-loop formation is contributing to the acceleration of CLL (Aim 2). Thus, targeting both RNA splicing and DNA damage response checkpoints are likely to provide synthetic cytotoxicity for CLLs with these lesions (Aim 3). Completion of the proposed work will create a fundamental foundation to explain how splicing factor mutations impact genomic instability and contribute to oncogenesis, and provide rationale for designing novel clinical trials in CLL patients with both SF3B1 mutations and ATM deletions.

项目概要全球测序工作已发现与疾病相关的反复出现的新型遗传病变进展、常见共现的推断模式以及响应克隆进化的特征慢性淋巴细胞白血病的治疗。尽管有大量可用的遗传信息，但这些分析所有这些都依赖于统计推断，从而限制了将基因型与表型联系起来的可能性。现在，了解高频遗传病变的功能以及它们如何与同时发生的疾病配合目前尚不清楚导致 CLL 起始和进展的突变。在本提案中，我们旨在了解如何 CLL 中最常见的两种遗传病变（SF3B1 突变和 ATM 缺失）会产生机械影响 CLL 的启动和进展，总体目标是了解 CLL 生物学、产生新型小鼠模型，并找到治疗这些病变的 CLL 的新策略。该提议基于我们的发现，即突变的 Sf3b1 与 Atm 缺失的共表达导致血液、骨髓和脾脏中克隆特征性 CD19+CD5+ B 细胞的发育，外显率较低老年（18个月）小鼠，可以通过体内传代繁殖。有趣的是，全基因组测序小鼠 CLL 的 DNA 分析显示染色体反复扩增，表明染色体不稳定一种导致 Sf3b1 突变和 Atm 缺失的小鼠 CLL 的机制。我们现在建议研究SF3B1突变通过RNA剪接相关的R-促进基因组不稳定的假设环形成，而 ATM 缺失通过减少 R 环相关性进一步增强基因组不稳定性 DNA 损伤修复（目标 1）。我们进一步假设 R 环形成的调制有助于 CLL 的加速（目标 2）。因此，针对 RNA 剪接和 DNA 损伤反应检查点是可能为具有这些病变的 CLL 提供合成细胞毒性（目标 3）。完成拟议的工作将为解释剪接因子突变如何影响基因组不稳定性奠定了基础有助于肿瘤发生，并为设计针对同时具有 SF3B1 的 CLL 患者的新型临床试验提供依据突变和 ATM 缺失。