Epigenetic Mechanisms Underpinning Mantle Cell Lymphoma Sensitivity and Resistance to Notch Inhibitors

项目摘要 功能获得性Notch突变是小B细胞淋巴瘤中最常见的突变，包括 慢性淋巴细胞白血病（CLL）和套细胞淋巴瘤（MCL）。携带Notch突变也是一种 小B细胞淋巴瘤预后不良的预测因子，尽管最近取得了进展， 化疗总之，这些观察结果为关注Notch抑制剂提供了令人信服的理由， 小B细胞淋巴瘤的潜在治疗选择。不幸的是，治疗Notch患者的进展 抑制剂一直受阻，部分原因是对敏感性的潜在机制的理解有限， 对Notch抑制剂的抗性。在这里，我们代表了一个共同的努力，以克服这些限制，并填补主要 通过测试我们的中心假设，即Notch驱动的激活和定位， 增强子协同Notch和几个关键的信号通路，共同激活促生长和存活基因 小B细胞淋巴瘤。这个前提是基于我们的初步数据，显示了一个重要的后果， Notch抑制是与关键基因相关的推定增强子元件的退役和重新定位 在原发性小B细胞淋巴瘤样本中，包括B细胞受体（BCR）和细胞因子的几种组分 信号通路我们将通过使用尖端的功能基因组学、染色质 构象捕获、基因组工程和单细胞分辨率基因组学和光学测定。我们将 系统地确定：i）Notch依赖性增强子激活和核定位，以及它们的基因组 共同介导Notch、BCR和细胞因子信号传导途径之间的串扰的要求; ii） Notch驱动的表观遗传程序的重新布线使耐药细胞能够绕过Notch抑制剂的影响 并维持关键Notch靶标的表达。这些互补研究将大大扩展 了解支持对Notch抑制剂敏感性和耐药性的表观遗传机制，并提供 在小B细胞淋巴瘤中靶向Notch的更清晰的理论基础。

Project Summary Gain-of-function Notch mutations are among the most frequent mutations in small B cell lymphomas, including chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). Harboring Notch mutation is also a predictor of poor outcomes in small B cell lymphomas, which despite recent advances remain incurable with chemotherapy. Together, these observations provide a compelling rationale for focusing on Notch inhibitors as potential therapeutic options in small B cell lymphomas. Unfortunately, progress in treating patients with Notch inhibitors has been stymied partly due to a limited understanding of underlying mechanisms of sensitivity and resistance to Notch inhibitors. Here, we represent a concerted effort to overcome these limitations and fill major gaps in current knowledge by testing our central hypothesis that Notch-driven activation and positioning of enhancers synergize Notch and several crucial signaling pathways to co-activate pro-growth and survival genes in small B cell lymphomas. This premise is based on our preliminary data showing an important consequence of Notch inhibition is decommissioning and repositioning of putative enhancer elements associated with key genes in primary small B cell lymphoma samples, including several components of B cell receptor (BCR) and cytokine signaling pathways. We will test this hypothesis by using cutting-edge functional genomics, chromatin conformation capture, genome engineering, and single-cell resolution genomics and optical assays. We will systematically determine: i) the Notch-dependent enhancer activation and nuclear positioning, and their genomic requirements that together mediate crosstalk between Notch, BCR and cytokine signaling pathways; ii) the rewiring of Notch-driven epigenetic program that enables drug-resistant cells to bypass effects of Notch inhibitors and maintain the expression of critical Notch targets. Together, these complementary studies will greatly expand understanding of epigenetic mechanisms underpinning sensitivity and resistance to Notch inhibitors and provide a clearer rationale for targeting Notch in small B cell lymphoma.