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.

项目摘要/摘要 费城染色体样B细胞急性淋巴细胞白血病（类似于pH）是一种亚型 不成比例地影响西班牙裔社区，其特征是对治疗的反应不佳， 退休的高风险，青少年和年轻人的峰值发作。在缺乏BCR-ABL融合时， 在细胞因子受体样因子2（CRLF2）基因中，将近65％的pH值所有病例都携带重排。 最常见的是带有免疫球蛋白重链基因座（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，所有pH都发生了 在68％的西班牙裔与23％的白人中，其中78％的西班牙裔患有与CRLF2相关的疾病 重排相比22％的白人，表明癌症差异明显。长期目标是 根据患者的遗传背景来开发预测性诊断，以解决癌症分布。 该提案的总体目标是利用B细胞病因的遗传和分子专业知识 确定CRLF2形成的机制的恶性肿瘤并确定如何改变 B细胞特异性因素和表观遗传印记的水平易于使用西班牙裔，因此 像pH一样。中心假设是DNA双链断裂（DSB）导致CRLF2-EIGH 易位是由涉及激活诱导的胞苷脱氨酶（AID）和DNA的机制产生的 甲基化以及对西班牙裔过程中这些过程的差异调节正在推动癌症差异。这 此项目步骤的基本原理，结果表明CRLF2 DSB导致CRLF2易位 高度富集在311 bp的簇区域。该群集中的DSB发生在辅助识别的主题上， 这些基序包含CpG序列，也是DNA甲基化位点。有证据表明mecis 脱氨基更有害于C月脱氨酸，并且更有可能导致DSB。确定是否 异常的辅助表达和变化的DNA甲基化模式解释了CRLF2形的形成增加 在西班牙裔中，至关重要的是解决所有pH的差异，并将通过三个具体目标进行测试：1） 定义CRLF2形成的分子机制； 2）确定遗传和表观遗传因素 基本的pH值像西班牙裔的所有分布； 3）开发一个分子测定以检测CRLF2-EGR 易位和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群集，新的应用 人类细胞中的分子和基因组技术，以解决所有pH的病因，并使用 UCI综合癌症中心的患者材料为大量西班牙裔人口提供服务。这项工作 很重要，因为它将解决西班牙裔社区中主要的癌症健康差异 诊断用于早期发现新疾病或中继疾病的诊断，同时拆开分子 不仅与pH的所有相关的机制，而且与其他几个B细胞恶量有关。