Oncogenic programs driven by Notch signaling in B-cell lymphoma

项目总结/摘要 尽管在B细胞淋巴瘤的临床治疗方面取得了进展，但具有某些高危遗传病变的患者仍不能完全治愈。 目前的治疗方法仍然效果不佳。基因中的复发性功能获得突变 编码Notch受体与侵袭性疾病和慢性胰腺炎患者存活率降低相关。 淋巴细胞白血病（CLL）和套细胞淋巴瘤（MCL）。Notch改变的致癌作用 信号传导可能是通过Notch转录因子激活基因调控靶点介导的 复杂，但在B细胞淋巴瘤中改变Notch信号传导的特异性靶点在很大程度上是未知的， 我们为这些患者设计合理治疗策略的能力。我最近用全基因组表观遗传学 分析以鉴定淋巴瘤亚型特异性增强子和增强子相关基因组重排 在来自不同B细胞淋巴瘤亚型的原发性肿瘤样本中（Cancer Discovery，2015）， 转录因子介导的增强子激活特定的癌基因程序。我将在 主要CLL和MCL标本，以及生理相关的体外和体内模型，以揭示 Notch信号传导的特异性基因靶点，并确定合作途径。我会用这种改良的生物 了解Notch在B细胞淋巴瘤中的作用，以设计和临床前测试新的策略， Notch驱动的淋巴瘤的治疗。 我是一名血液病理学家，对转录调控基因的改变有着浓厚的研究兴趣 B细胞淋巴瘤的生物学。我未来几年的主要职业目标是获得终身教职 在学术医学中心担任研究实验室首席研究员。我在找K 08 支持马萨诸塞州总医院布拉德利伯恩斯坦博士实验室的指导研究/ 布罗德研究所，由布里格姆妇女医院的乔恩·阿斯特博士和丹娜·法伯共同指导 癌症研究所.一个K 08奖将给我保护的时间来推进我的研究计划，发展 在全基因组数据集的生物分析方面的额外技能，并进行专门培训， 使用生理学相关小鼠模型进行淋巴瘤研究的经验。我至少会 我80%的时间集中在Notch信号转导和转录机制的研究调查上， 调节B细胞淋巴瘤，高达20%的时间致力于血液学的临床诊断 恶性肿瘤，以及教学和培训的追求。马萨诸塞州总医院 麻省理工学院和哈佛大学、布里格姆妇女医院和丹娜-法伯癌症研究所都是机构 在生物医学研究和研究培训领域享有国际声誉，并拥有 许多在淋巴恶性肿瘤、转录和表观遗传调控方面造诣很深的专家， 实验治疗学马萨诸塞州总医院的病理科有一个 在独立癌症研究人员的培训，以及开发和使用 癌症诊断的先进分子工具。我已经组建了一个由当地专家组成的咨询小组， 我的项目的重要性，包括凯瑟琳·吴博士，X博士。雪莉·刘和大卫·温斯托克博士 建议我进行这项研究，以及我的职业发展。我发起了合作 与其他学术医生和科学家谁将提供具体的资源和指导，以促进我的 研究（欧文伯恩斯坦博士，Notch激活的体外建模，A. John Iafrate，分子 诊断和生物标志物，和Ephraim Hochberg博士，淋巴瘤临床治疗研究）。我有 制定了一个结构化的职业发展计划，包括在实验室的培训和指导 管理，科学领导，研究沟通，拨款写作和其他关键的职业技能。 总之，本建议书的要素将为我提供所需的经验、培训和指导 成为一名成功的独立医生，科学家，临床重点是淋巴瘤诊断， 在基础和转化淋巴瘤生物学的生产研究生涯。

PROJECT SUMMARY / ABSTRACT Despite advances in the clinical treatment of B-cell lymphoma, patients with certain high-risk genetic lesions continue to have poor outcomes with current therapies. Recurrent gain-of-function mutations in genes encoding Notch receptors are associated with aggressive disease and decreased survival in chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). The oncogenic effects of altered Notch signaling are likely mediated through activation of gene regulatory targets by the Notch transcription factor complex, but the specific targets of altered Notch signaling in B-cell lymphoma are largely unknown, limiting our ability to devise rational treatment strategies for these patients. I recently used genome-wide epigenetic profiling to identify lymphoma subtype-specific enhancers and enhancer-associated genomic rearrangements in primary tumor samples from diverse B-cell lymphoma subtypes (Cancer Discovery, 2015), linking transcription factor-mediated enhancer activation to specific oncogene programs. I will extend this approach in primary CLL and MCL specimens, as well as physiologically relevant in vitro and in vivo models, to uncover the specific gene targets of Notch signaling and identify cooperating pathways. I will use this improved biological understanding of the role of Notch in B-cell lymphomas to design and pre-clinically test novel strategies for the treatment of Notch-driven lymphomas. I am a hematopathologist with a strong research interest in the role of altered transcriptional regulatory genes in the biology of B-cell lymphoma. My primary career objective in the coming years is to obtain a tenure-track position at an academic medical center as a research laboratory Principal Investigator. I am seeking K08 support for mentored research in the laboratory of Dr. Bradley Bernstein at Massachusetts General Hospital / Broad Institute, with co-mentorship from Dr. Jon Aster at Brigham and Women’s Hospital and Dana-Farber Cancer Institute. A K08 award would give me protected time to advance my research program, to develop additional skills in the biological analysis of genome-wide data sets, and to pursue specialized training and experience in the use of physiologically relevant mouse models for the study of lymphoma. I will devote at least 80% of my time to a focused research investigation into the mechanisms of Notch signaling and transcriptional regulation in B cell lymphomas, with up to 20% of my time devoted to the clinical diagnosis of hematological malignancies, as well as teaching and training pursuits. Massachusetts General Hospital, Broad Institute of MIT and Harvard University, Brigham and Women’s Hospital, and Dana-Farber Cancer Institute are institutions of international renown in the fields of biomedical research and research training, and host the laboratories of many highly accomplished experts in lymphoid malignancy, transcriptional and epigenetic regulation, and experimental therapeutics. The Department of Pathology at Massachusetts General Hospital has a distinguished history in the training of independent cancer researchers, and the development and use of advanced molecular tools for cancer diagnosis. I have assembled an advisory team of local experts in areas of importance to my project, consisting of Dr. Catherine Wu, Dr. X. Shirley Liu, and Dr. David Weinstock, who will advise me in the conduct of this research, as well as my career development. I have initiated collaborations with other academic physicians and scientists who will provide specific resources and guidance to advance my investigations (Dr. Irwin Bernstein, in vitro modeling of Notch activation, Dr. A. John Iafrate, molecular diagnostics and biomarkers, and Dr. Ephraim Hochberg, clinical therapeutic research in lymphoma). I have formulated a structured career development plan that includes training and mentorship in laboratory management, scientific leadership, research communication, grant writing, and other critical career skills. Together, the elements of this proposal will provide me with the experience, training, and mentorship needed to become a successful independent physician-scientist with a clinical focus on lymphoma diagnostics, and a productive research career in basic and translational lymphoma biology.