Oncogenic Roles and Therapeutic Potential of MCL1 Addiction in Primary Effusion Lymphoma

项目摘要 原发性渗出性淋巴瘤是一种由DNA肿瘤病毒Kaposi‘s引起的侵袭性B细胞淋巴瘤 肉瘤相关疱疹病毒(KSHV)。PEL是一种不寻常的癌症，因为没有复发的突变 在肿瘤中有报道。相反，PEL需要病毒编码的癌基因的持续表达来改变 潜伏感染细胞的细胞转录组。候选方法给我们留下了一个有限的视角 细胞癌基因是病毒性淋巴瘤所必需的。没有有效和特异的治疗方法也就不足为奇了 可用于治疗这种疾病。我们最近已经确定了210个人类基因，称为PEL特异性致癌基因 依赖关系(PSOD)，这对这些肿瘤来源的细胞系的生存至关重要，使用 全基因组CRISPR/Cas9筛选。我们已经证明，PEL细胞系表现出对 抗凋亡蛋白MCL1，尽管有高水平的其他相关的BCL2蛋白。的新功能 MCL1已经开始独立于其在防止细胞凋亡中的典型作用而出现。目前尚不清楚是否 这种对MCL1的选择性要求超过了其他BCL2蛋白，这是因为需要阻止特定的细胞凋亡 应激或MCL1是否在PEL中发挥非规范功能。然而，我们已经表明，我们可以 使用小分子化合物S63845通过药物抑制MCL1来利用这种依赖性。 在目标1中，我将测试S63845在异种移植小鼠模型中治疗PEL的治疗潜力。在目标2中，我 将调查PEL对MCL1上瘾的原因。具体地说，在目标2a中，我将研究MCL1在阻断中的作用 P53抑癌基因家族的活性。在目标2B中，我将采取不偏不倚的方法并执行 CRISPR筛选以确定MCL1的遗传交互作用。总而言之，我期待这项研究将发现新的 对MCL1生物学的总体洞察，回答为什么MCL1在PEL中很重要，并将MCL1开发为 这种癌症的新治疗靶点。完成这一奖项将为我的职业生涯开辟新的研究领域 病毒淋巴瘤的独立调查员。

Project Summary Primary effusion lymphoma (PEL) is an aggressive B cell lymphoma caused by the DNA tumor virus Kaposi’s sarcoma-associated herpesvirus (KSHV). PEL is an unusual cancer in that no recurrent mutations have been reported in tumors. Instead, PEL requires the continued expression of virally encoded oncogenes to alter the cellular transcriptome in latently infected cells. Candidate approaches have left us with a limited view of what cellular oncogenes are required by the viral lymphoma. It is not surprising that no effective and specific therapy is available to treat this disease. We have recently identified 210 human genes, called PEL-specific oncogenic dependencies (PSODs), that are critically important for the survival of these tumor-derived cell lines using genome-wide CRISPR/Cas9 screens. We have shown that PEL cell lines exhibit a specialized requirement for the anti-apoptotic protein MCL1 despite having high levels of other related BCL2 proteins. New functions of MCL1 have started to emerge independent of its canonical role in preventing apoptosis. It is not clear whether this selective requirement for MCL1 over the other BCL2 proteins is due to a need to block a specific apoptotic stress or whether MCL1 plays a non-canonical function in PEL. Nevertheless we have shown that we can leverage this dependency by pharmacologically inhibiting MCL1 using the small molecule compound S63845. In Aim 1, I will test the therapeutic potential of S63845 for treating PEL in a xenograft mouse model. In Aim 2, I will investigate why PEL is addicted to MCL1. Specifically in Aim 2A, I will study the role of MCL1 in blocking the activities of the p53 tumor suppressor family. In Aim 2B, I will take an unbiased approach and perform CRISPR screens to identify genetic interactions of MCL1. Together, I expect that this study will uncover new insights into the biology of MCL1 in general, answer why MCL1 is important in PEL, and develop MCL1 as a new therapeutic target for this cancer. Completion of this award will open new research areas for my career as an independent investigator in viral lymphomas.