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是一种以广泛克量增殖和恶性B淋巴细胞的积累为特征的疾病 在血液中，骨髓，囊和淋巴结。 CLL显示出显着的临床异质性，有些 追求懒惰的患者，而其他患者则迅速进展并需要早期治疗。在过去的10个 多年来，对线粒体脂质激酶，酰基甘油激酶（AGK）的生物学功能的新见解为A 关键的癌基因在一系列肿瘤类型中高度表达，包括前列腺癌，乳腺癌， 已经建立了宫颈鳞状细胞癌和食管鳞状细胞癌。最多 最近，我们发现约60％的疗法CLL患者的CLL细胞异常高的AGK表达。 但是，CLL细胞中AGK异常上调的机制及其精度功能贡献 CLL细胞生物学和发病机理仍然未知。有趣的是，我们检测到核/细胞质 AGK在某些CLL克隆中的定位表明其多功能作用。与此相一致，我们发现sirna- AGK在原代CLL细胞中的介导的部署导致了对组成型活性倍数的明显抑制 信号介质包括AKT，ERK1/2，LYN，BTK（BCR信号的下游目标）和JAK2。我们的 初步发现还表明MYC可能调节CLL细胞中的AGK表达。我们的组合数据 表明AGK的异常表达可能在某些中可能具有BCR和JAK2在内的潜在细胞存活信号 CLL克隆导致对BCR靶向疗法的抗性。因此，该应用的中心假设 在某些CLL克隆中，AGK的异常表达代表高度攻击性的CLL，时间较短 治疗。我们还假设AGK上调的电势CLL细胞存活信号和对BCR-的抵抗力 目标代理。我们建议 - 目标1：评估CLL细胞中AGK的异常表达是否驱动疾病 进展；目标2：定义AGK上调的机制及其在CLL细胞生物学，信号传导和 作为治疗靶标的潜力。拟议的深入研究将评估CLL细胞中的“高AGK”水平是否服务 作为CLL进展，治疗时间和治疗结果的危险因素；定义AGK异常的影响 CLL细胞存活和对当前BCR靶向疗法的抗性的表达。那是拟议的研究 通过针对AGK建立新的预后参数和治疗途径，具有巨大的潜力 具有或没有当前BCR靶向治疗的CLL细胞，Ibrutinib。