Targeting the Notch:Myc axis in leukemia/lymphoma

靶向Notch：白血病/淋巴瘤中的Myc轴

• 批准号: 10322391
• 负责人: WARREN S PEAR
• 金额: $ 44.95万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10322391
• 关键词: Acute Myelocytic Leukemia; Acute T Cell Leukemia; B-Cell Leukemia; B-Cell Neoplasm; B-Lymphocytes; Binding; Binding Sites; Biological Assay; Cell Proliferation; Cell Survival; Cells; ChIP-seq; Defect; Disease; Distal; Drug resistance; Elements; Enhancers; Family; GATA3 gene; Genetic Transcription; Goals; Growth; Hematopoietic Neoplasms; Human; IRF1 gene; Individual; Lead; MYC gene; Malignant - descriptor; Malignant Neoplasms; Mantle Cell Lymphoma; Mediating; Metabolic; Metabolism; Mus; Mutation; Oncogenes; Oncogenic; Play; Proto-Oncogenes; Refractory; Regulation; Relapse; Reporter; Research; Resistance; Role; Signal Transduction; Stretching; T-Cell Development; T-Cell Leukemia; T-Lymphocyte; TCF3 gene; Transcription Elongation; Transcriptional Regulation; Work; YY1 Transcription Factor; acute myeloid leukemia cell; cell type; drug sensitivity; gamma secretase; genetic element; inhibitor; insight; leukemia/lymphoma; lymphoid neoplasm; new therapeutic target; notch protein; novel; novel strategies; patient derived xenograft model; prevent; promoter; recruit; resistance mechanism; selective expression; transcription factor; tumor

Project Summary Activating Notch mutations are found in both human T cell acute lymphoblastic leukemia cases (T-ALL) and B cell leukemias/lymphomas including Mantle Cell Lymphoma (MCL). A direct transcriptional target of Notch in both malignancies is the proto-oncogene Myc, which is the most frequently amplified oncogene across a wide range of malignancies as it has critical roles in gene transcription, metabolism, cell proliferation and survival. In the proposed work, we will characterize Myc transcriptional regulation in both T-ALL and MCL. We previously identified a distal (1.3 Mb 3' to the promoter) T cell specific Myc enhancer region termed the Notch-Dependent Myc Enhancer (NDME), that is active in a reporter assay and loops to the Myc promoter in mouse and human T-ALL cells. At least four T cell transcription factors bind in this region, however, their role in activating the NDME is unknown. Previous work from our lab showed that T-ALL cells created to be resistant to Notch inhibition maintain Myc expression through a switch in enhancer usage to another region, termed the Brd4- Dependent Myc Enhancer (BDME). A potential treatment for T-ALL is the BET family inhibitor JQ1, which has already proved efficacious in AML. We generated JQ1-resistant human T-ALL cells that maintain MYC expression. Unlike the T cell NDME, the B cell NDME is located ~500 kb 5' to the Myc promoter and surrounded by B cell specific transcription factors. The goal of this proposal is to understand Notch-dependent Myc regulation in both T-ALL and MCL. In particular, we will determine how Notch regulates Myc enhancer states in T-ALL and MCL and identify factors that cooperate with Notch to “set-up” and maintain the T cell and B cell NDMEs. In addition to elucidating the function of these enhancers, we will determine how Myc enhancer states dictate drug sensitivity and resistance in T-ALL cells. Together, This work will provide critical insights into the mechanisms of Myc regulation in leukemia and lymphoma and may identify novel targets for treating both de novo and refractory T-ALL and MCL. !

项目摘要 在人T细胞急性淋巴细胞白血病病例（T-ALL）和B中都发现了激活的Notch突变 细胞性白血病/淋巴瘤，包括地幔细胞淋巴瘤（MCL）。 Notch的直接转录目标 这两种恶性肿瘤都是原始癌基因MYC，它是宽阔的癌基因最常见的癌基因 恶性肿瘤范围在基因转录，代谢，细胞增殖和存活中具有关键作用。在 拟议的工作，我们将在T-All和MCL中表征MYC转录调节。我们以前 鉴定出远端（启动子1.3 Mb 3'）T细胞特异性MYC增强子区域称为Notch依赖性 MYC增强器（NDME），在记者测定中活跃，并向MYC启动子循环鼠标和人类循环 T-ALL细胞。但是，至少有四个T细胞转录因子在该区域结合，但是它们在激活中的作用 NDME是未知的。我们实验室的先前工作表明，创建的T-ALL细胞具有对缺口的抗性 抑制作用通过向另一个区域的增强子使用中的开关维持MYC表达，称为BRD4-- 依赖MYC增强器（BDME）。 T-All的潜在治疗方法是BET家族抑制剂JQ1，它具有 已经证明在AML中有效。我们生成了维持MYC的耐JQ1的人T-ALL细胞 表达。与T细胞NDME不同，B细胞NDME位于MYC启动子和 被B细胞特异性转录因子包围。该建议的目的是了解依赖于Notch T-ALL和MCL中的MYC调节。特别是，我们将确定Notch如何调节MYC增强器 T-All和MCL中的各州，并确定用Notch教练以“设置”并维护T细胞的因素 B细胞ndmes。除了阐明这些增强剂的功能外，我们还将确定MYC增强器的方式 状态决定了T-ALL细胞中的药物敏感性和耐药性。这项工作将共同提供关键的见解 进入白血病和淋巴瘤中MYC调节的机制，并可能确定治疗的新靶 从头和难治性的T-All和Mcl均均已。 呢