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

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， 不成比例地影响西班牙裔社区，并被表征为对治疗反应差， 复发的风险高，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（CRLF 2）基因重排， 最常见的是免疫球蛋白重链基因座（CRLF 2-IgH）的染色体易位 导致CRLF 2的过度表达和低存活率。一项比较研究发现， 在68%的西班牙裔和23%的白人中，78%的西班牙裔患有与CRLF 2相关的疾病， 与22%的白人相比，这表明了明显的癌症差异。长期目标是 根据患者的遗传背景开发预测性诊断，以解决癌症差异。的 该提案的总体目标是利用B细胞病因学的遗传和分子专业知识 恶性肿瘤，以确定CRLF 2-IgH形成的机制，并确定如何改变 B细胞特异性因子和表观遗传印记水平使西班牙裔人易发生这种易位， Ph样ALL。核心假设是DNA双链断裂（DSB）导致CRLF 2-IgH 易位是由激活诱导的胞苷脱氨酶（AID）和DNA 甲基化和这些过程在西班牙裔中的差异调节正在推动癌症的差异。的 该项目的基本原理源于结果显示CRLF 2 DSB导致CRLF 2-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， 这些基序含有也是DNA甲基化位点的CpG序列。有证据表明， 脱氨作用比C2 H4脱氨作用更有害，并且更可能导致DSB。确定是否 AID的异常表达和DNA甲基化模式的改变导致CRLF 2-IgH形成增加 在西班牙裔美国人中，对解决Ph样ALL差异至关重要，并将通过三个具体目标进行测试：1） 明确CRLF 2-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Ph样ALL差异; 3）开发检测CRLF 2-IgH的分子测定 易位，并比较西班牙裔和非西班牙裔的治疗反应。的创新方面 这项工作是鉴定与CRLF 2不稳定性相关的311 bp DSB簇，应用新的 分子和基因组技术在人类细胞中的应用，以解决Ph样ALL的病因，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。这项工作 是重要的，因为它将解决一个主要的癌症健康差距在西班牙裔社区，并开发一种新的 早期诊断新的或复发的疾病，同时解开分子 这一机制不仅与Ph样ALL相关，而且与其他几种B细胞恶性肿瘤相关。

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.