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

项目摘要/摘要 费城染色体样B细胞急性淋巴细胞白血病(Ph-like ALL)是一种ALL亚型 对西班牙裔社区的影响不成比例，并被认为对治疗反应不佳， 复发风险高，青少年和青壮年发病高峰期。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， 最常见的是带有免疫球蛋白重链基因的染色体易位(CRLF2-IgH) 导致CRLF2过度表达，存活率低。一项比较研究发现，类Ph都发生在 在68%的西班牙裔和23%的白人中，78%的拉美裔有与CRLF2相关的疾病 相比之下，白人的这一比例为22%，显示出明显的癌症差异。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。这个 这项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改变 B细胞特异性因子的水平和表观遗传印记使拉美裔人容易发生这种易位，因此 像所有人一样。中心假设是DNA双链断裂(DSB)导致CRLF2-IgH 易位是由激活诱导的胞苷脱氨酶(AID)和DNA引起的 甲基化和拉美裔人对这些过程的不同调控是导致癌症差异的原因。这个 这个项目的基本原理源于结果表明CRLF2 DSB导致CRLF2-IGH易位 在311个碱基团簇区高度富集区。该簇中的DSB出现在由AID识别的基序和 这些基序包含CpG序列，这些序列也是DNA甲基化的位点。有证据表明，MECT 脱氨基比C--U脱氨基更有害，更有可能导致DSB。确定是否 异常的AID表达和DNA甲基化模式变化是CRLF2-IgH形成增加的原因 在拉美裔美国人中是解决Ph式所有差异的关键，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 3)建立检测CRLF2-IgH的分子检测方法 并比较拉美裔和非拉美裔患者的治疗反应。的创新方面 这项工作是鉴定与CRLF2不稳定性有关的311个碱基的DSB星团，新的应用 人类细胞的分子和基因组技术，以解决类Ph ALL的病因学，并使用 患者材料来自UCI综合癌症中心，该中心服务于大量西班牙裔人口。这部作品 意义重大，因为它将解决拉美裔社区的主要癌症健康差距，并开发一种新的 早期诊断新的或复发的疾病，同时解开一种分子 这一机制不仅与类Ph ALL有关，而且还与其他几种B细胞恶性肿瘤有关。

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.