Study Pro-Oncogenic Role of BCL6 in CLL Tumorigenesis

研究 BCL6 在 CLL 肿瘤发生中的促癌作用

• 批准号: 10661814
• 负责人: Asish Kumar Ghosh
• 金额: $ 19.93万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-07 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10661814
• 关键词: Accounting; Adaptive Immune System; Adult; Agammaglobulinaemia tyrosine kinase; Antigens; Applications Grants; Automobile Driving; B lymphoid malignancy; B-Cell Activation; B-Cell Antigen Receptor; B-Cell Lymphoma 6 Protein; B-Lymphocytes; BCL2 gene; BCL6 gene; BMI1 gene; Behavior; Biological; Biology; Blood; Bone Marrow; CCND1 gene; Cell Proliferation; Cell Survival; Cells; Cellular biology; Chronic Lymphocytic Leukemia; Clinical; DNA Damage; Data; Dedications; Development; Diagnosis; Disease; Disease Progression; Early treatment; Epigenetic Process; Event; Generations; Genes; Genetic; Genetic Transcription; Goals; Heat-Shock Proteins 90; Heterogeneity; Human; In Vitro; Indolent; Induction of Apoptosis; Innate Immune System; Investigation; LYN gene; Malignant - descriptor; Mediator; Messenger RNA; Molecular; Mus; Mutation; Oncogenes; Oncogenic; Oral; PI3K/AKT; PLCgamma2; Pathogenesis; Pathway interactions; Patient-Focused Outcomes; Patients; Play; Process; Proliferating; Proteins; Proto-Oncogenes; Public Health; Receptor Signaling; Regulation; Reporting; Repression; Resistance; Richter' s Syndrome; Risk Factors; Role; Signal Transduction; Spleen; Structure of germinal center of lymph node; TP53 gene; Testing; Therapeutic; Time; Transcription Repressor; Transgenic Organisms; Treatment outcome; Tumor Burden; Tumor Suppressor Genes; Up-Regulation; axl receptor tyrosine kinase; chronic lymphocytic leukemia cell; clinical heterogeneity; cohort; gene repression; high risk; improved; in vivo; inhibitor; inhibitor therapy; innovation; large cell Diffuse non-Hodgkin' s lymphoma; leukemia; lymph nodes; lymphoid neoplasm; mouse model; novel; overexpression; prognostic; programs; promoter; relapse patients; survival outcome; targeted agent; targeted treatment; therapy outcome; therapy resistant; tumorigenesis

PROJECT SUMMARY Chronic lymphocytic leukemia (CLL) is an adult B-cell malignancy accounting for about a third of leukemia diagnoses in the US. While B-cell receptor (BCR)-signal-inhibitors are changing the management of CLL, these are not curative and resistance can develop; often leading to more aggressive disease. Given this, understanding the molecular events driving CLL oncogenesis and therapeutic resistance warrants in-depth investigation. CLL shows remarkable clinical heterogeneity, with some patients pursuing an indolent course, while others progress rapidly and require early treatment. Extensive heterogeneity exists also at the genetic, epigenetic, and transcriptional level. In addition to constitutively active BCR signal, we previously reported the existence of a highly active receptor tyrosine kinase (RTK) AXL in CLL cells regulating multiple signal mediators including LYN, PI3K/AKT and PLCγ2 thus, potentiating CLL cell survival signals. B-cell lymphoma 6 (BCL6) is a transcriptional repressor and proto-oncogene that plays a crucial role in the innate and adaptive immune system and lymphoid neoplasms, regulating numerous genes involved in DNA damage and cell proliferation. Most recently, we have detected expression of BCL6 in CLL cells from previously untreated CLL patients both at mRNA and protein levels. Our preliminary findings indicate that HSP90 overexpression may regulate BCL6 protein levels in CLL cells. Importantly, our initial data also suggest that aberrant expression of BCL6 may regulate the highly active AXL survival signal in CLL cells. However, the mechanism of aberrant upregulation of BCL6 in CLL cells, and its precise functional contributions to CLL biology and disease pathogenesis are poorly understood. It is also not clear if the target transcriptional landscape of aberrantly expressed BCL6 in CLL cells is different than that is detected in normal germinal center B-cells. Therefore, the central hypothesis of this application is that overexpression of BCL6 in CLL cells represents highly aggressive disease with shorter time to therapy. We also postulate that BCL6 upregulation potentiates CLL cell survival signals and resistance to BCR-targeted agents. We propose – Aim 1: Evaluate if BCL6 upregulation in CLL cells drives disease progression; Aim 2: Define the mechanism of BCL6 upregulation and its role in CLL cell biology and signaling. The proposed in-depth studies will assess if “high BCL6” level in CLL cells serves as a risk factor for CLL progression, time to therapy and treatment outcome; define the impact of BCL6 aberrant expression on CLL cell survival and resistance to current BCR-targeted therapies. Thus, the proposed studies have great potential to establish a new prognostic parameter and therapeutic avenue via targeting BCL6 in CLL cells in combination with the current BCR-targeted therapy, ibrutinib.

项目概要 慢性淋巴细胞白血病 (CLL) 是一种成人 B 细胞恶性肿瘤，约占白血病的三分之一 虽然 B 细胞受体 (BCR) 信号抑制剂正在改变 CLL 的治疗，但这些 没有治疗作用，并且会产生耐药性；鉴于此，请理解。 驱动 CLL 肿瘤发生和治疗耐药的分子事件值得深入研究。 CLL 表现出显着的临床异质性，一些患者病程缓慢，而另一些患者则表现出明显的临床异质性 进展迅速，需要早期治疗，在遗传、表观遗传和遗传方面也存在广泛的异质性。 除了组成型活跃的 BCR 信号外，我们之前报道了转录水平的存在。 CLL 细胞中的高活性受体酪氨酸激酶 (RTK) AXL 调节多种信号介质，包括 LYN、 因此，PI3K/AKT 和 PLCγ2 增强了 CLL 细胞的存活信号。 B 细胞淋巴瘤 6 (BCL6) 是一种转录抑制基因和原癌基因，在先天性免疫反应中发挥着至关重要的作用。 和适应性免疫系统和淋巴肿瘤，调节涉及 DNA 损伤的众多基因 最近，我们在之前未经治疗的 CLL 细胞中检测到了 BCL6 的表达。 CLL 患者的 mRNA 和蛋白质水平均表明 HSP90 过度表达。 重要的是，我们的初始数据还表明 BCL6 蛋白水平的异常表达。 BCL6可能调节CLL细胞中高度活跃的AXL生存信号，但其机制存在异常。 CLL 细胞中 BCL6 的上调及其对 CLL 生物学和疾病的精确功能贡献 人们对发病机制知之甚少，也不清楚目标转录景观是否异常。 CLL 细胞中表达的 BCL6 与正常生发中心 B 细胞中检测到的不同。 本申请的中心假设是 CLL 细胞中 BCL6 的过度表达代表高度侵袭性 我们还假设 BCL6 上调可增强 CLL 细胞的存活率。 我们建议 – 目标 1：评估 BCL6 在 CLL 细胞中是否上调。 驱动疾病进展；目标 2：明确 BCL6 上调机制及其在 CLL 细胞生物学中的作用 和信号。 拟议的深入研究将评估 CLL 细胞中的“高 BCL6”水平是否是 CLL 的危险因素 进展、治疗时间和治疗结果；定义 BCL6 异常表达对 CLL 细胞的影响； 因此，拟议的研究具有巨大的潜力。 通过联合靶向 CLL 细胞中的 BCL6 建立新的预后参数和治疗途径 目前的 BCR 靶向疗法 ibrutinib（依鲁替尼）。