G0S2 in Chronic Myeloid Leukemia Disease Progression and Imatinib Resistance

G0S2 在慢性粒细胞白血病疾病进展和伊马替尼耐药中的作用

基本信息

批准号：
10223599
负责人：
Anna Marie Eiring
金额：
$ 19.56万
依托单位：
TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER AT EL PASO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-10 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10223599
关键词：
ABL1 gene Acute leukemia Address Apoptosis Arterial Occlusive Diseases Binding Biological CD34 gene Cell Line Cell Survival Cell physiology Cells Cellular Assay Chemicals Chronic Chronic Disease Chronic Myeloid Leukemia Chronic Phase Clinical Data Deletion Mutation Development Disease Disease Progression Disease remission Down-Regulation Drug resistance Economic Burden Epigenetic Process Failure Fatty Acids Gene Expression Profile Genes Genetic Transcription Genus Hippocampus Glycolysis Goals Growth Human Hypermethylation Imatinib Impairment In Vitro Knockout Mice Lead Life Link Maps Mediating Metabolic Pathway Methylation Molecular Morbidity - disease rate Mus Mutation Oncogenic Oxidative Phosphorylation Pathway interactions Patients Peripheral Pharmaceutical Preparations Phase Phenotype Phosphotransferases Play Point Mutation Prevalence Protein Tyrosine Kinase Proteins Publishing Quality of life Recurrence Regulation Reporting Research Residual state Resistance Role Signal Pathway Technology Testing Transcription Repressor Transgenic Mice Tyrosine Kinase Inhibitor Xenograft procedure advanced disease alternative treatment career career development catalyst chronic myeloid leukemia cell effective therapy improved in vivo inhibitor/antagonist knock-down leukemia leukemic stem cell leukemogenesis lipid metabolism mRNA Expression metabolic profile mouse model novel novel therapeutic intervention patient response programs promoter response side effect small hairpin RNA success therapeutic target treatment strategy

项目摘要

PROJECT SUMMARY/ABSTRACT Chronic myeloid leukemia (CML) is caused by BCR-ABL1, a constitutively active tyrosine kinase. The development of tyrosine kinase inhibitors (TKIs) targeting BCR-ABL1 has revolutionized the treatment of CML, turning it from a fatal into a manageable chronic condition. Many patients respond favorably to TKIs, but some patients do not achieve a response, and others lose their response, for an overall estimated failure rate of 20- 30% in chronic phase (CP-CML), and even higher rates in advanced CML. While TKI resistance is commonly linked to point mutations in the BCR-ABL1 kinase domain, ~50% of clinical resistance cannot be explained by BCR-ABL1 mutations, suggesting BCR-ABL1 kinase-independent resistance. Recurrence of active CML after discontinuation of TKIs in responding patients is thought to reflect persistence of quiescent leukemic stem cells (LSCs) that are innately resistant to TKIs despite BCR-ABL1 inhibition. Thus, understanding the molecular mechanisms underlying BCR-ABL1 kinase-independent resistance will be critical to identify alternative treatment strategies for patients with TKI resistance or advanced CML and to eradicate disease. Microarray data revealed downregulation of G0S2 mRNA expression in CML CD34+ cells from imatinib non-responders (without mutations) compared to responders, and in advanced disease compared to chronic phase. Preliminary data suggests that G0S2 may play a role in both primary TKI resistance and in blastic transformation of CML. Specific Aim 1: Determine whether G0S2 loss promotes TKI resistance and disease progression in CML. Data from this aim will investigate the functional consequence of G0S2 loss in TKI resistance and blastic transformation. We will assess the role of G0S2 in the growth, survival, and TKI sensitivity of CML cell lines and primary CML CD34+ cells both in vitro and in vivo. We will also utilize a BCR-ABL1 transgenic mouse model and G0S2 null mice to assess the role of G0S2 in CML leukemogenesis in vivo. Specific Aim 2: Identify the mechanism by which loss of G0S2 induces TKI resistance in CML. G0S2 has been implicated in metabolic pathway regulation, including fatty acid synthesis and oxidative phosphorylation. We have formed a collaborative research team to rigorously establish the mechanistic role of G0S2 downregulation in TKI resistance. We will address how reduced expression of G0S2 influences these metabolic pathways and, in turn, whether these pathways alter imatinib response. Specific Aim 3: Determine the mechanism(s) by which G0S2 is downregulated in TKI resistance and identify strategies to restore G0S2 expression. Data from this aim will identify how G0S2 is downregulated in TKI resistance and blastic transformation, and will identify ways of reprogramming TKI-resistant cells into a TKI-sensitive phenotype. We will investigate the potential role of promoter hypermethylation and binding of transcriptional repressors, as well as the contribution of known oncogenic signaling pathways. These studies will be crucial for developing novel treatment approaches for TKI- resistant CML patients and other drug-resistant leukemias, and will launch my independent research career.

项目概要/摘要慢性粒细胞白血病 (CML) 是由 BCR-ABL1（一种持续活跃的酪氨酸激酶）引起的。这针对 BCR-ABL1 的酪氨酸激酶抑制剂 (TKI) 的开发彻底改变了 CML 的治疗，将其从致命的疾病转变为可控制的慢性疾病。许多患者对 TKI 反应良好，但有些患者患者没有获得反应，其他人则失去反应，总体估计失败率为 20- 慢性期 (CP-CML) 为 30%，晚期 CML 的比例甚至更高。虽然 TKI 耐药性普遍存在与 BCR-ABL1 激酶结构域中的点突变有关，约 50% 的临床耐药性不能用以下方法解释： BCR-ABL1 突变，表明 BCR-ABL1 激酶无关的耐药性。活动性 CML 复发后对有反应的患者停用 TKI 被认为反映了静态白血病干细胞的持续存在尽管 BCR-ABL1 受到抑制，但 LSCs 对 TKI 具有天然耐药性。因此，了解分子 BCR-ABL1 激酶独立耐药性的潜在机制对于确定替代治疗至关重要针对 TKI 耐药或晚期 CML 患者的策略并根除疾病。微阵列数据揭晓伊马替尼无反应者的 CML CD34+ 细胞中 G0S2 mRNA 表达下调（无反应）突变）与应答者相比，以及晚期疾病与慢性期相比。初步数据表明 G0S2 可能在原发性 TKI 耐药和 CML 的急变转化中发挥作用。具体的目标 1：确定 G0S2 缺失是否会促进 CML 中 TKI 耐药和疾病进展。数据出于这个目的，我们将研究 G0S2 缺失在 TKI 耐药性和急变性中的功能后果。转变。我们将评估 G0S2 在 CML 细胞系的生长、存活和 TKI 敏感性中的作用，并体外和体内原代 CML CD34+ 细胞。我们还将利用 BCR-ABL1 转基因小鼠模型 G0S2 缺失小鼠评估 G0S2 在体内 CML 白血病发生中的作用。具体目标 2：确定 G0S2 缺失导致 CML 中 TKI 耐药的机制。 G0S2 与代谢有关途径调节，包括脂肪酸合成和氧化磷酸化。我们已经形成了协作研究小组严格建立了 G0S2 下调在 TKI 耐药中的机制作用。我们将解决 G0S2 表达减少如何影响这些代谢途径，以及这些代谢途径是否途径改变伊马替尼反应。具体目标 3：确定 G0S2 的机制 TKI 耐药性下调并确定恢复 G0S2 表达的策略。来自该目标的数据将确定 G0S2 在 TKI 抗性和急变转化中如何下调，并将确定将 TKI 耐药细胞重编程为 TKI 敏感表型。我们将调查潜在的作用启动子高甲基化和转录抑制子的结合，以及已知的贡献致癌信号通路。这些研究对于开发新的 TKI 治疗方法至关重要耐药CML患者和其他耐药白血病患者，并将展开我的独立研究生涯。