Oncogenic programs driven by Notch signaling in B-cell lymphoma

项目摘要/摘要 尽管B细胞淋巴瘤的临床治疗取得了进展，但患有某些高危基因损害的患者 目前的治疗方法仍然效果不佳。基因中反复出现的功能增益突变 编码Notch受体与慢性侵袭性疾病和生存率下降有关 淋巴细胞性白血病(CLL)和套细胞淋巴瘤(MCL)。改良切迹的致癌作用 信号转导可能是通过Notch转录因子激活基因调控靶标来实现的 复杂，但B细胞淋巴瘤中Notch信号改变的特定靶点大多未知，限制了 我们有能力为这些患者设计合理的治疗策略。我最近使用了全基因组的表观遗传学 识别淋巴瘤亚型特异性增强子和增强子相关基因组重排的图谱 在不同B细胞淋巴瘤亚型的原发肿瘤样本中(癌症发现，2015)，链接 转录因子介导的特定癌基因程序的增强子激活。我将在以下方面扩展此方法 原代CLL和MCL标本，以及与生理相关的体外和体内模型，以揭示 Notch信号的特异性基因靶点和识别协同作用的途径。我会用这个改良过的生物 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治疗策略 切迹淋巴瘤的治疗。 我是一名血液病理学家，对转录调节基因改变的作用有着浓厚的研究兴趣。 在B细胞淋巴瘤的生物学方面。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的职位。我在找K08 支持马萨诸塞州综合医院布拉德利·伯恩斯坦博士实验室的指导研究 布罗德研究所，布里格姆妇女医院的乔恩·阿斯特博士和Dana-Farber共同指导 癌症研究所。K08奖将给我有保障的时间来推进我的研究计划，开发 在全基因组数据集的生物学分析方面的其他技能，并进行专门的培训和 使用生理相关的小鼠模型研究淋巴瘤的经验。我至少会致力于 我80%的时间专注于Notch信号和转录机制的研究 B细胞淋巴瘤的调节，我有多达20%的时间用于血液学的临床诊断 癌症，以及教学和培训方面的追求。马萨诸塞州总医院，博德学院 麻省理工学院和哈佛大学、布里格姆妇女医院和达纳-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，并主办 许多在淋巴系统恶性肿瘤、转录和表观遗传调控方面非常有成就的专家，以及 实验治疗学。马萨诸塞州综合医院的病理科有一个 在培训独立癌症研究人员以及开发和使用 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顾问团队，他们的领域包括 对我的项目的重要性，由Catherine Wu博士、X.Shirley Liu博士和David Weinstock博士组成，他将 在这项研究的进行以及我的职业发展方面给我提供建议。我已经发起了协作 与其他学术医生和科学家一起，他们将提供具体的资源和指导，以推进我的 研究(欧文·伯恩斯坦博士，Notch激活的体外建模，A.John Iafrate博士，分子 诊断和生物标记物，以及Ephraim Hochberg博士，淋巴瘤临床治疗研究)。我有过 制定了结构化的职业发展计划，其中包括实验室培训和指导 管理、科学领导、研究交流、拨款撰写和其他关键的职业技能。 综上所述，这项提案的内容将为我提供所需的经验、培训和指导 成为一名成功的独立内科医生兼科学家，专注于淋巴瘤诊断的临床研究，并 从事基础和转译淋巴瘤生物学方面的富有成效的研究工作。

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.