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: 10512700
• 负责人: Asish Kumar Ghosh
• 金额: $ 16.95万
• 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/10512700
• 关键词: Accounting; Adaptive Immune System; Adult; Agammaglobulinaemia tyrosine kinase; Antigens; Apoptosis; 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; Development; Diagnosis; Disease; Disease Progression; Early treatment; Emu species; Epigenetic Process; Event; Generations; Genes; Genetic; Genetic Transcription; Goals; Heat-Shock Proteins 90; Heterogeneity; Human; In Vitro; Indolent; Investigation; LYN gene; Malignant - descriptor; Mediator of activation protein; Messenger RNA; Molecular; Mus; Mutation; Oncogenes; Oncogenic; Oral; PI3K/AKT; PLCgamma2; Pathogenesis; Pathway interactions; Patient Agents; Patient-Focused Outcomes; Patients; Play; Process; Proteins; Proto-Oncogenes; Public Health; Receptor Signaling; Regulation; Reporting; Resistance; 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.

项目摘要 慢性淋巴细胞白血病（CLL）是成人B细胞恶性肿瘤，约占白血病的三分之一 在美国的诊断。而B细胞受体（BCR） - 信号抑制剂正在改变CLL的管理 无法治愈，耐药性会发展；通常导致更具侵略性的疾病。鉴于这一点，理解 驱动CLL肿瘤发生和热耐药的分子事件需要深入研究。 CLL表现出显着的临床异质性，有些患者正在追求懒惰的过程，而另一些患者则 迅速进展并需要早期治疗。在遗传，表观遗传和 转录级别。除组成性活性BCR信号外，我们先前报道了A 在CLL细胞中，高度活跃的受体酪氨酸激酶（RTK）AXL调节多个信号介质，包括Lyn， 因此，PI3K/AKT和PLCγ2因此，潜在的CLL细胞存活信号。 B细胞淋巴瘤6（BCl6）是转录复制品和原始癌基因，在先天性中起着至关重要的作用 以及自适应免疫学系统和淋巴肿瘤，调节许多参与DNA损伤的基因 和细胞增殖。最近，我们从以前未处理的CLL细胞中检测到BCl6的表达 mRNA和蛋白质水平的CLL患者。我们的初步发现表明HSP90过表达可能 调节CLL细胞中的Bcl6蛋白水平。重要的是，我们的初始数据还表明 BCl6可以调节CLL细胞中高度活跃的AXL存活信号。但是，异常机制 BCL6在CLL细胞中的上调及其对CLL生物学和疾病的精确功能贡献 发病机理知之甚少。还不清楚目标转录格局是否异常 在CLL细胞中表达的BCl6与在正常生发中心B细胞中检测到的Bcl6不同。因此， 该应用的中心假设是CLL细胞中BCl6的过表达代表高度侵略性 治疗时间较短。我们还假设Bcl6上调电势CLL细胞存活 信号和对BCR靶向剂的抵抗力。我们建议 - 目标1：评估CLL细胞中的BCl6是否上调 推动疾病进展；目标2：定义BCl6上调的机制及其在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 生存和对当前BCR靶向疗法的抵抗力。那就是拟议的研究有很大的潜力 通过在CLL细胞中靶向BCL6建立新的预后参数和热大道 与当前的BCR靶向疗法，Ibrutinib。