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

淋巴瘤是一种癌症，通常是由一种叫做生发中心B细胞的免疫系统细胞的恶性转化引起的。最具侵袭性的淋巴瘤亚型与癌基因MYC的遗传激活有关，对现有治疗的反应较差。迫切需要更有效、毒性更小的新疗法。RNA解旋酶是一种解除其目标信使RNA内二级结构的蛋白质。我们实验室最近的数据表明，RNA解旋酶DDX3X和它的y染色体旁系物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驱动的淋巴瘤细胞经常将它们的依赖性从无处不在的DDX3X转换到y染色体前导DDX3Y，这是一种通常只在睾丸中表达的蛋白质。这种平行开关是由DDX3X的基因失活引起的，接着是DDX3Y的异位激活。作为正常细胞中缺失的癌症必需基因，DDX3Y代表了一个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具有冗余性，但新出现的数据表明，这两种方言之间可能存在重要的功能差异。该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细胞来研究DDX3X和DDX3Y的功能。这些将与先进的分析技术相结合，以确定两种解旋酶在正常和恶性B细胞中的对比功能。这项工作将剖析DDX3X和DDX3Y在mRNA加工的每个阶段的共同和平行特异性作用，并阐明DDX3Y异位表达的机制。同时，我们将识别由旁导开关赋予淋巴瘤细胞的合成脆弱性。总的来说，这项研究将建立生物学上的理解，以利用获得性ddx3y依赖性作为侵袭性B细胞淋巴瘤的一种新的治疗易感性。

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.