Genomic profiling of AIDS-related Plasmablastic lymphoma

描述(申请人提供)：浆母细胞性淋巴瘤(PL)是人类免疫缺陷病毒(HIV)感染患者中最常见的口腔恶性肿瘤之一，尽管使用了高效抗逆转录病毒疗法(HAART)和弥漫性大B细胞淋巴瘤的标准化疗(CHOP方案)，但预后非常差。重要的是，在引入HAART后，PL的发生率显著增加。根据WHO的分类，PL被归类为弥漫性大B细胞淋巴瘤(DLBCL)的一个亚型，它与HIV和Epstein Barr病毒显著相关。我们假设，PL的一个重要亚群，如果不是全部，在生物学上更像浆细胞骨髓瘤(PCM)，而不是DLBCL。在初步研究中，我们已经表明，PL和PCM具有几乎不可区分的免疫表型表达谱。 作为检验我们假设的第一步，R21提案的主要目标是评估艾滋病相关PL、DLBCL(艾滋病相关和非艾滋病相关)和PCM之间的遗传异同。我们将应用我们和其他人最近开发的基于阵列的比较基因组杂交(阵列CGH)技术，允许高通量分析DNA拷贝数偏差，以确定这些肿瘤的基因组图谱。基因组水平的发现随后将在蛋白质组水平上进行初步检查。如果这项拟议研究的结果支持我们的假设，我们将在下一阶段的研究(R01拨款申请)中以更大的样本量证实这些发现。如果我们的假设在下一阶段的研究中得到证实，可能会考虑将一部分与艾滋病相关的PL患者用于针对PCM的治疗方案，以改善治疗结果。我们的长期目标是：1)阐明艾滋病相关PL的发病机制；2)识别有助于检测AIDS相关PL及其进展的可靠的诊断和预后生物标志物；3)开发新的靶向治疗药物，以预防和/或治疗PL。最终，我们可能能够消除艾滋病患者因这种目前致命的疾病而遭受的痛苦。

DESCRIPTION (provided by applicant): Plasmablastic lymphoma (PL), one of the most frequent oral malignancies in human immunodeficiency virus (HIV) infected patients, has very poor prognosis despite the use of highly active antiretroviral therapy (HAART) and standard chemotherapy for diffuse large B-cell lymphoma (CHOP based regimen). Importantly, the incidence of PL has significantly increased following the introduction of HAART. By WHO Classification, PL is categorized as a subtype of diffuse large B-cell lymphoma (DLBCL) which is notably associated with HIV and Epstein Barr virus. We hypothesize that a significant subset, if not all, of PL is biologically more like plasma cell myelomas (PCM) than DLBCL. In preliminary studies, we have shown that PL and PCM share almost indistinguishable immunophenotypic expression profiles. As the initial step to test our hypothesis, the main goal of this R21 proposal is to evaluate the genetic similarities and differences among AIDS-related PL, DLBCL (AIDS-related and non AIDS-related) and PCM. We will apply array-based comparative genomic hybridization (array CGH) technology, recently developed by us and others, allowing the high-throughput analysis of DNA copy number aberrations, to determine the genomic profiles of these tumors. The findings at the genome level will then be preliminarily examined at proteome levels. If the results of this proposed study support our hypothesis, we will confirm these findings in the next phase (an R01 grant application) of study with a larger sample size. If our hypothesis is substantiated in the next phase of study, a subset of patients with AIDS-related PL may be considered for the therapeutic regimens against PCM to improve treatment outcome. Building on the findings of the first genome-wide analysis of AIDS-related PL outlined in this proposal, our long-term goals are: 1) to elucidate the pathogenesis of AIDS-related PL, 2) to identify reliable diagnostic and prognostic biomarkers useful for detection of AIDS-related PL and its progression and 3) to develop novel agents for targeted therapies to prevent and/or treat PL. Ultimately, we may be able to eliminate suffering of AIDS patients from this currently deadly disease.