RNA helicases; switched paralogue dependency as an exploitable vulnerability in aggressive B cell lymphoma.

RNA解旋酶；

• 批准号: EP/Y030303/1
• 负责人: Daniel Hodson
• 金额: $ 215.76万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FY030303%2F1
• 关键词: RNA; helicases; switched; paralogue; dependency

Lymphoma is form of cancer arising most often from the malignant transformation of a specific type of immune system cell called the germinal centre B cell. The most aggressive subtypes of lymphoma are associated with genetic activation of the oncogene MYC, and respond poorly to available therapies. New treatments that are more effective and less toxic are urgently required. RNA helicases are proteins that unwind secondary structure within their target messenger RNAs. Recent data from our lab suggest the RNA helicase DDX3X and its Y-chromosome paralogue DDX3Y are at the centre of an intriguing lymphoma-specific vulnerability. We showed that male MYC-driven lymphoma cells often switch their dependency from the ubiquitous DDX3X, to the Y-chromosome prologue DDX3Y, a protein normally expressed only in the testis. This paralogue switch results from the genetic inactivation of DDX3X, followed by ectopic activation of DDX3Y. As a cancer-essential gene absent from normal cells, DDX3Y represents an exciting tumour-specific, therapeutic target. However, little is known about the molecular activity or regulation of DDX3Y. Despite a prior assumption of redundancy with DDX3X, emerging data suggests there may be important functional differences between the two paralogues. This project will investigate the functions of DDX3X and DDX3Y using a series of genetically modified mouse models, engineered cell lines and primary human B cells. These will be combined with advanced analytical techniques to determine the contrasting functions of the two helicases in normal and malignant B cells. This work will dissect the shared and paralogue-specific roles of DDX3X and DDX3Y in each stage of mRNA processing and elucidate the mechanisms of DDX3Y ectopic expression. In parallel, we will identify the synthetic vulnerabilities conferred upon lymphoma cells by the paralogue switch. Overall, this study will build the biological understanding required to exploit acquired DDX3Y-dependency as a novel therapeutic vulnerability of aggressive B cell lymphoma.

淋巴瘤是癌症的一种形式，最常见的是一种称为生发中心B细胞的特定类型的免疫系统细胞的恶性转化。最具侵袭性的淋巴瘤亚型与致癌基因MYC的遗传激活相关，并且对可用的疗法反应不佳。迫切需要更有效、毒性更小的新治疗方法。RNA解旋酶是在其靶信使RNA内解旋二级结构的蛋白质。我们实验室的最新数据表明，RNA解旋酶DDX3X及其Y染色体副产物DDX3Y是一个有趣的淋巴瘤特异性脆弱性的中心。我们发现，男性MYC驱动的淋巴瘤细胞通常将其依赖性从普遍存在的DDX3X转换为Y染色体序言DDX3Y，这是一种通常仅在睾丸中表达的蛋白质。这种异位转换是由于DDX3X的遗传失活，随后是DDX3Y的异位激活。作为正常细胞中不存在的癌症必需基因，DDX3Y代表了令人兴奋的肿瘤特异性治疗靶点。然而，对DDX3Y的分子活性或调控知之甚少。尽管先前假设DDX3X存在冗余，但新出现的数据表明，这两种旁系同源物之间可能存在重要的功能差异。本项目将利用一系列转基因小鼠模型、工程细胞系和原代人B细胞研究DDX 3X和DDX 3Y的功能。这些将与先进的分析技术相结合，以确定两个解旋酶在正常和恶性B细胞中的对比功能。本工作将剖析DDX3X和DDX3Y在mRNA加工的每个阶段中的共享和旁系同源特异性作用，并阐明DDX3Y异位表达的机制。与此同时，我们将确定由paramount开关赋予淋巴瘤细胞的合成脆弱性。总体而言，这项研究将建立所需的生物学理解，利用获得性DDX 3 Y依赖性作为一种新的治疗侵袭性B细胞淋巴瘤的脆弱性。