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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：
10597240
负责人：
Lili Wang
金额：
$ 41.52万
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/10597240
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 Chemoresistance Chromosomal Instability Chromosomes Chronic Lymphocytic Leukemia Clinic Clinical Trials Clonal Evolution Clonal Expansion DNA DNA Damage DNA Repair DNA Repair Pathway DNA damage checkpoint DNA sequencing Data Dependence Development Disease Progression Excision Foundations Frequencies Genes Genetic Genomic Instability Genotype Goals Heterozygote 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 cancer cell 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.

项目总结