Defining the Mechanism of Genome Rearrangements in Ph-Like ALL to Determine Predictive Markers in High-Risk Hispanic Populations

定义 Ph 样 ALL 基因组重排机制以确定高危西班牙裔人群的预测标记

• 批准号: 10570932
• 负责人: Nicholas Pannunzio
• 金额: $ 41.66万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-14 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10570932
• 关键词: Acute Lymphocytic Leukemia; Address; Adolescent and Young Adult; Advocate; Affect; Automobile Driving; B lymphoid malignancy; B-Cell Acute Lymphoblastic Leukemia; B-Lymphocytes; Biological Assay; CRISPR/Cas technology; California; Catchment Area; Cells; Chromosomal translocation; Clinical; Collecting Cell; Communities; Comparative Study; Comprehensive Cancer Center; Cytokine Receptors; Cytosine; DNA Double Strand Break; DNA Methylation; DNA Repair; Data; Deamination; Diagnosis; Diagnostic; Disease; Disease remission; Disparity; Doxycycline; Early Diagnosis; Early Intervention; Enzyme Activation; Epigenetic Process; Ethnic Origin; Etiology; Fostering; Gene Expression; General Population; Genes; Genetic; Genome; Genomic Instability; Genomics; Goals; Health; Heavy-Chain Immunoglobulins; Hispanic; Hispanic Populations; Human; IGH@ gene cluster; Incidence; Knowledge; Latino Population; Link; Maps; Methods; Methylation; Mission; Modification; Molecular; Mutation; Not Hispanic or Latino; Oncogenes; Patients; Philadelphia Chromosome; Population; Predisposing Factor; Prevalence; Prevention; Prevention strategy; Preventive Medicine; Process; Public Health; Recurrent disease; Regulation; Research; Risk; Role; Sampling Studies; Site; Survival Rate; Techniques; Testing; Time; United States National Institutes of Health; Whole Blood; Work; activation-induced cytidine deaminase; bcr-abl Fusion Proteins; bisulfite sequencing; cancer health disparity; cancer risk; community living; digital; effective therapy; experimental study; genome-wide; health disparity; high risk; hispanic community; human disease; imprint; improved; improved outcome; individualized prevention; innovation; lectures; lentiviral integration; meetings; methylation pattern; mortality; novel; novel diagnostics; overexpression; personalized medicine; personalized predictions; predictive marker; relapse risk; repaired; stem; treatment comparison; treatment response

PROJECT SUMMARY/ABSTRACT Philadelphia chromosome-like B cell acute lymphoblastic leukemia (Ph-like ALL) is an ALL subtype that disproportionately affects the Hispanic community and is characterized as having a poor response to therapy, a high risk of relapse, and a peak onset in adolescents and young adults. While lacking a BCR-ABL fusion, nearly 65% of Ph-like ALL cases carry a rearrangement in the cytokine receptor-like factor 2 (CRLF2) gene, the most common being a chromosomal translocation with the immunoglobulin heavy chain locus (CRLF2-IgH) resulting in overexpression of CRLF2 and low survival. One comparative study found that Ph-like ALL occurred in 68% of Hispanics versus 23% of Whites and of those, 78% of Hispanics had disease associated with CRLF2 rearrangements compared to 22% of Whites, indicating a clear cancer disparity. The long-term goal is to develop predictive diagnostics based upon a patient’s genetic background to address cancer disparities. The overall objectives for this proposal are to leverage genetic and molecular expertise on the etiology of B cell malignancies to determine the mechanism underlying CRLF2-IgH formation and determine how changing levels of B cell-specific factors and epigenetic imprinting predispose Hispanics to this translocation and thus Ph-like ALL. The central hypothesis is that DNA double-strand breaks (DSBs) leading to CRLF2-IgH translocations result from a mechanism involving activation-induced cytidine deaminase (AID) and DNA methylation and that differential regulation of these processes in Hispanics is driving the cancer disparity. The rationale for this project stems from results showing that CRLF2 DSBs resulting in CRLF2-IgH translocations are highly enriched in a 311 bp cluster region. DSBs within this cluster occur at motifs recognized by AID and these motifs contain CpG sequences that are also sites of DNA methylation. Evidence shows that meCT deamination is more detrimental that CU deamination and more likely to result in DSBs. Determining if aberrant AID expression and changing DNA methylation patterns account for increased CRLF2-IgH formation in Hispanics is critical in addressing the Ph-like ALL disparity and will be tested through three specific aims: 1) Define the molecular mechanism of CRLF2-IgH formation; 2) Determine genetic and epigenetic factors underlying Ph-like ALL disparities in Hispanics; and 3) Develop a molecular assay to detect CRLF2-IgH translocations and compare treatment response in Hispanics and non-Hispanics. The innovative aspects of this work are identification of a 311 bp DSB cluster associated with CRLF2 instability, application of new molecular and genomic techniques in human cells to address the etiology of Ph-like ALL, and the use of patient material from the UCI comprehensive cancer center that serves a large Hispanic population. This work is significant as it will address a major cancer health disparity in the Hispanic community and develops a novel diagnostic for early detection of new or relapsed disease while at the same time unravelling a molecular mechanism that is not only relevant to Ph-like ALL, but also to several additional B cell malignancies.

项目概要/摘要 费城染色体样 B 细胞急性淋巴细胞白血病（Ph 样 ALL）是一种 ALL 亚型， 对西班牙裔社区的影响尤为严重，其特点是对治疗反应不佳， 复发风险很高，并且在青少年和年轻人中发病高峰。虽然缺乏 BCR-ABL 融合， 近 65% 的 Ph 样 ALL 病例携带细胞因子受体样因子 2 (CRLF2) 基因重排， 最常见的是免疫球蛋白重链位点 (CRLF2-IgH) 的染色体易位 导致 CRLF2 过度表达和低存活率。一项比较研究发现，Ph 样 ALL 发生 68% 的西班牙裔人患有与 CRLF2 相关的疾病，而白人中这一比例为 23%，其中 78% 的西班牙裔人患有与 CRLF2 相关的疾病 与 22% 的白人相比，这种情况发生了重排，表明存在明显的癌症差异。长期目标是 根据患者的遗传背景开发预测诊断，以解决癌症差异。这 该提案的总体目标是利用 B 细胞病因学方面的遗传和分子专业知识 恶性肿瘤以确定 CRLF2-IgH 形成的机制并确定如何变化 B 细胞特异性因子和表观遗传印记的水平使西班牙裔人容易发生这种易位，因此 Ph 样 ALL。核心假设是 DNA 双链断裂 (DSB) 导致 CRLF2-IgH 易位是由涉及激活诱导的胞苷脱氨酶 (AID) 和 DNA 的机制引起的 甲基化以及西班牙裔人对这些过程的差异调节正在推动癌症差异。这 该项目的基本原理源于结果表明 CRLF2 DSB 导致 CRLF2-IgH 易位 在 311 bp 的簇区域高度富集。该簇内的 DSB 出现在 AID 识别的基序处，并且 这些基序包含 CpG 序列，也是 DNA 甲基化位点。有证据表明 meCT 脱氨基作用比 CU 脱氨基作用更有害，并且更有可能导致 DSB。确定是否 异常的 AID 表达和改变的 DNA 甲基化模式导致 CRLF2-IgH 形成增加 西班牙裔人口的差异对于解决类似博士生的所有差异至关重要，并将通过三个具体目标进行测试：1) 明确CRLF2-IgH形成的分子机制； 2）确定遗传和表观遗传因素 西班牙裔中潜在的类似Ph的所有差异； 3) 开发一种分子检测方法来检测 CRLF2-IgH 易位并比较西班牙裔和非西班牙裔的治疗反应。创新的方面 这项工作是识别与 CRLF2 不稳定性相关的 311 bp DSB 簇，应用新的 人类细胞中的分子和基因组技术，以解决 Ph 样 ALL 的病因学，以及使用 来自 UCI 综合癌症中心的患者材料，该中心为大量西班牙裔人口提供服务。这部作品 意义重大，因为它将解决西班牙裔社区中主要的癌症健康差异，并开发出一种新颖的方法 早期发现新发疾病或复发疾病的诊断，同时揭示分子机制 该机制不仅与 Ph 样 ALL 有关，而且与其他几种 B 细胞恶性肿瘤有关。