Pro-Oncogenic Role of a Mitochondrial Lipid Kinase in CLL

线粒体脂质激酶在 CLL 中的促癌作用

• 批准号: 10651077
• 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: 2023
• 资助国家: 美国
• 起止时间: 2023-04-10 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10651077
• 关键词: Accounting; Adult; Agammaglobulinaemia tyrosine kinase; Antigens; Applications Grants; Automobile Driving; B lymphoid malignancy; B-Cell Activation; B-Cell Antigen Receptor; B-Lymphocytes; BCL2 gene; Behavior; Binding; Biological; Biological Process; Blood; Bone Marrow; Cell Proliferation; Cell Survival; Cells; Cellular biology; Cervical Squamous Cell Carcinoma; Chronic Lymphocytic Leukemia; Clinical; Cytoplasm; Data; Dedications; Diagnosis; Diglycerides; Disease; Disease Progression; Early treatment; Epigenetic Process; Esophageal Squamous Cell Carcinoma; Event; FRAP1 gene; Genetic; Genetic Transcription; Goals; Heterogeneity; Human; In Vitro; Indolent; Induction of Apoptosis; Investigation; JAK2 gene; LYN gene; Lipids; Liposomes; Malignant - descriptor; Malignant neoplasm of prostate; Mediating; Mediator; Mitochondria; Molecular; Monoglycerides; Nuclear; Oncogenes; Oncogenic; Oral; Organ; PI3K/AKT; PIK3CG gene; PTEN gene; Pathogenesis; Pathway interactions; Patient-Focused Outcomes; Patients; Phosphatidic Acid; Phosphotransferases; Process; Production; Proliferating; Proto-Oncogene Proteins c-akt; Public Health; Receptor Inhibition; Receptor Signaling; Regulation; Resistance; Richter' s Syndrome; Risk Factors; Role; STAT3 gene; Signal Transduction; Signaling Molecule; Small Interfering RNA; Spleen; Squamous cell carcinoma; Testing; Therapeutic; Time; Transgenic Mice; Treatment outcome; Tumor Burden; Up-Regulation; cell growth; cell type; chronic lymphocytic leukemia cell; clinical heterogeneity; cohort; cytotoxic; high risk; improved; in vivo; inhibitor; inhibitor therapy; innovation; insight; kinase inhibitor; large cell Diffuse non-Hodgkin' s lymphoma; leukemia; lymph nodes; lysophosphatidic acid; malignant breast neoplasm; mitochondrial membrane; mouse model; novel; overexpression; prognostic; relapse patients; survival outcome; targeted agent; targeted treatment; therapeutic target; therapy outcome; therapy resistant; tumor; 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 is a disease characterized by extensive clonal proliferation and accumulation of malignant B lymphocytes in the blood, bone marrow, spleen, and lymph nodes. CLL shows remarkable clinical heterogeneity, with some patients pursuing an indolent course, while others progress rapidly and require early treatment. In the past 10 years, new insights into the biological function of a mitochondrial lipid kinase, acylglycerol kinase (AGK), as a key oncogene that is highly expressed in a range of tumor types, including prostate cancer, breast cancer, cervical squamous cell carcinoma, and esophageal squamous cell carcinoma have been established. Most recently, we found aberrantly high level expression of AGK in CLL cells from ~60% of pre-therapy CLL patients. However, the mechanism of aberrant upregulation of AGK in CLL cells, and its precise functional contributions to CLL cell biology and pathogenesis remain unknown. Interestingly, we detected nuclear/cytoplasmic localization of AGK in some CLL clones suggesting its multi-functional role. In line with this, we found that siRNA- mediated depletion of AGK in primary CLL cells resulted in marked inhibition of constitutively active multiple signal mediators including AKT, Erk1/2, LYN, BTK (downstream targets of BCR signal) and JAK2. Our preliminary findings also indicate that MYC may regulate AGK expression in CLL cells. Our combined data suggest that aberrant expression of AGK may potentiate cell survival signals including BCR and JAK2 in some CLL clones resulting in resistance to BCR-targeted therapies. Therefore, the central hypothesis of this application is that aberrant expression of AGK in some CLL clones represents highly aggressive CLL with shorter time to therapy. We also postulate that AGK upregulation potentiates CLL cell survival signals and resistance to BCR- targeted agents. We propose – Aim 1: Evaluate if aberrant expression of AGK in CLL cells drives disease progression; Aim 2: Define the mechanism of AGK upregulation and its role in CLL cell biology, signaling and potential as a therapeutic target. The proposed in-depth studies will assess if “high AGK” level in CLL cells serves as a risk factor for CLL progression, time to therapy and treatment outcome; define the impact of AGK aberrant expression on CLL cell survival and resistance to current BCR-targeted therapies. Thus, the proposed studies have enormous potential to establish a new prognostic parameter and therapeutic avenue via targeting AGK in CLL cells with or without 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是一种以恶性B淋巴细胞克隆性增殖和广泛积累为特征的疾病 血液、骨髓、脾脏和淋巴结中的 CLL 表现出显着的临床异质性，其中一些。 过去10年里，一些患者病情进展缓慢，而另一些患者则进展迅速，需要早期治疗。 多年来，人们对线粒体脂质激酶、酰基甘油激酶 (AGK) 的生物学功能有了新的认识。 在一系列肿瘤类型中高表达的关键癌基因，包括前列腺癌、乳腺癌、 宫颈鳞状细胞癌和食管鳞状细胞癌已确诊最多。 最近，我们发现约 60% 治疗前 CLL 患者的 CLL 细胞中 AGK 异常高水平表达。 然而，CLL 细胞中 AGK 异常上调的机制及其精确的功能贡献 CLL 的细胞生物学和发病机制仍不清楚。 AGK 在一些 CLL 克隆中的定位表明其具有多功能作用，我们发现 siRNA- 原代 CLL 细胞中 AGK 介导的耗竭导致组成型活性多重细胞的显着抑制 信号介体包括 AKT、Erk1/2、LYN、BTK（BCR 信号的下游靶标）和 JAK2。 初步研究结果还表明 MYC 可能调节 CLL 细胞中的 AGK 表达。 表明 AGK 的异常表达可能会增强一些细胞存活信号，包括 BCR 和 JAK2 CLL 克隆导致对 BCR 靶向疗法的耐药性，因此，这是本申请的中心假设。 一些 CLL 克隆中 AGK 的异常表达代表了高度侵袭性的 CLL，且治疗时间较短 我们还假设 AGK 上调可增强 CLL 细胞存活信号和对 BCR-的抵抗力。 我们建议 – 目标 1：评估 CLL 细胞中 AGK 的异常表达是否会导致疾病。 目标 2：明确 AGK 上调的机制及其在 CLL 细胞生物学、信号传导和疾病中的作用。 拟议的深入研究将评估 CLL 细胞中“高 AGK”水平是否有效。 作为 CLL 进展的危险因素，治疗时间和治疗结果定义了 AGK 异常的影响； 表达对 CLL 细胞存活和对当前 BCR 靶向疗法的耐药性的影响。 通过靶向 AGK 在建立新的预后参数和治疗途径方面具有巨大的潜力 使用或不使用当前 BCR 靶向疗法 ibrutinib（依鲁替尼）的 CLL 细胞。