Activation-induced deaminase as a mutator oncogene

激活诱导的脱氨酶作为突变癌基因

• 批准号: 7140111
• 负责人: Andrea Bottaro
• 金额: $ 13.1万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7140111
• 关键词: Activation; induced; deaminase; mutator; oncogene

DESCRIPTION (provided by applicant): Activation induced deaminase (AID) is expressed in normal activated B-lymphocytes, where it is required for immunoglobulin (Ig) gene somatic hypermutation (SHM) and class switch recombination (CSR). While AID bears significant similarity to the RNA editing enzyme APOBEC-1, recent findings suggest that it may act directly on DNA, changing cytidine residues into uridine. This application is based on the hypothesis that loss of regulation of AID activity results in somatic hypermutation affecting the entire genome, instead of being highly targeted to Ig genes. As such, deregulated AID could act as a mutator oncogene, contributing to neoplastic development and progression, specifically in B cell malignancies. In support of this model is the finding that AID is constitutively expressed in many human B cell leukemias and lymphomas, although in these samples AID expression is often uncoupled from active SHM of Ig genes, suggesting functional deregulation. Significantly, alternatively spliced AID mRNAs, capable of encoding truncated AID isoforms lacking regions that are thought to be involved in substrate targeting, are reproducibly found in B cell neoplastic samples. Finally, ubiquitous AID overexpression in transgenic mice results in T cell lymphomas, but - surprisingly - not B cell neoplasias. A gain-of-function mutator phenotype as the one hypothesized here would represent a novel pathogenetic mechanism, and would suggest that AID may be a useful target for pharmacological intervention to curtail neoplastic progression. In this respect, several known and likely inhibitors of cytidine deaminases have already been characterized, and could find rapid clinical application. Based on structural and functional studies, we predict that truncated AID isoforms will display altered targeting patterns, or dominantly disrupt targeting of wild-type AID. We propose to specifically test the potential effects of truncated AID isoforms on SHM activity is indeed deregulated in malignant B cells, and to investigate the effect of expression of truncated AID isoforms on SHM and CSR activity. To formally prove the causal involvement of AID in B cell malignancy we will generate new transgenic mice in which AID expression will recapitulate the pattern observed in some diffuse large B cell lymphomas. Finally, we will test a series of drug candidates for their ability to suppress AID cytidine deaminase activity as a prelude to future targeted pharmacological interventions.

描述(申请人提供)：激活诱导脱氨酶(AID)在正常激活的B淋巴细胞中表达，是免疫球蛋白(Ig)基因体细胞超突变(SHM)和类开关重组(CSR)所必需的。虽然AID与RNA编辑酶APOBEC-1有很大的相似之处，但最近的发现表明，它可能直接作用于DNA，将胞苷残基改变为尿苷。这一应用是基于这样一种假设，即失去对AID活性的调节会导致影响整个基因组的体细胞超突变，而不是高度针对Ig基因。因此，去调控的AID可以作为突变癌基因，促进肿瘤的发展和进展，特别是在B细胞恶性肿瘤中。支持这一模型的是，许多人类B细胞白血病和淋巴瘤中都有AID的结构性表达，尽管在这些样本中，AID的表达往往与Ig基因的活性SHM解偶联，这表明功能去调节。值得注意的是，选择性剪接的AID mRNAs能够编码截短的AID亚型，缺少被认为参与底物靶向的区域，在B细胞肿瘤样本中可重复发现。最后，转基因小鼠中普遍存在的艾滋病过度表达会导致T细胞淋巴瘤，但令人惊讶的是，它不会导致B细胞肿瘤。这里假设的功能获得突变子表型将代表一种新的致病机制，并提示AID可能是药物干预抑制肿瘤进展的有用靶点。在这方面，几种已知的和可能的胞苷脱氨酶抑制剂已经被表征，并可能很快在临床上应用。基于结构和功能的研究，我们预测截短的AID亚型将显示改变的靶向模式，或主要干扰野生型AID的靶向。我们建议特异性地测试截短的AID亚型对恶性B细胞SHM活性的潜在影响，并研究截短的AID亚型表达对SHM和CSR活性的影响。为了正式证明AID与B细胞恶性肿瘤的因果关系，我们将产生新的转基因小鼠，在其中AID的表达将概括一些弥漫性大B细胞淋巴瘤中观察到的模式。最后，我们将测试一系列候选药物抑制AID胞苷脱氨酶活性的能力，作为未来有针对性的药物干预的前奏。

项目成果

The biologic properties of leukemias arising from BCR/ABL-mediated transformation vary as a function of developmental origin and activity of the p19ARF gene.

由 BCR/ABL 介导的转化引起的白血病的生物学特性随着 p19ARF 基因的发育起源和活性而变化。

• DOI: 10.1182/blood-2008-02-142190
• 发表时间: 2008
• 期刊: Blood
• 影响因子: 20.3
• 作者: Wang,Pin-Yi;Young,Fay;Chen,Chun-Yu;Stevens,BrettM;Neering,SarahJ;Rossi,RandallM;Bushnell,Timothy;Kuzin,Igor;Heinrich,David;Bottaro,Andrea;Jordan,CraigT
• 通讯作者: Jordan,CraigT