Project title: Targeting autophagy and aberrant mitochondrial folate metabolism in leukemic stem cells

项目名称：针对白血病干细胞中的自噬和异常线粒体叶酸代谢

• 批准号: 2611201
• 金额: --
• 依托单位: University of Glasgow
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2611201
• 关键词: Project; title; Targeting; autophagy; aberrant

Chronic myeloid leukemia (CML) is a myeloproliferative disease consisting of a small number of cancer-causing leukemic stem cells (LSCs) and a variety of mature progenitors. LSCs represent the top of the differentiation hierarchy, responsible for the accumulation of blast cells and driving hematologic relapse. CML development begins with the acquisition of the Philadelphia chromosome (Ph) in a singular pluripotent hematopoietic stem cell (HSC). The Ph is a fusion of chromosomes 9 and 22, causing the formation of BCR-ABL, the chimeric proto-oncogene responsible for HSC transformation. BCR-ABL is a constituently active tyrosine kinase (TK), whose activity perturbs and enhances pathways well established to be involved in the cancer signalling, such as JAK/STAT, PI3K/AKT and RAS/MEK. The CML therapeutic landscape is dominated by tyrosine kinase inhibitors (TKIs), blocking the interactions between BCR-ABL and ATP thus abolishing downstream signalling pathways. The first TKI developed to treat CML in such a way was imatinib, developed and trialled in the late 1990s, to this day it still remains a standard treatment. The majority of patients treated with imatinib in the chronic phase respond strongly to treatment, with BCR-ABL transcripts drastically lowering in abundance with the potential to reach undetectable levels. A study by O'Brien et al., 2003 showed that after 18 months of treatment with imatinib, 87.1% of patients showed a major cytogenic response, while 76.2% of patients showed a complete cytogenic response. Despite patients showing excellent responses to TKI treatment, discontinuation of imatinib treatment is frequently followed by cytogenic and hematologic relapse, suggesting that BCR-ABL inhibition on its own is not a curative approach. Most CML patients require lifelong TKI treatment to prevent relapse, this is far from ideal given the vascular complications caused by second generation TKIs and the potential for the development of secondary resistance. It is hypothesised that relapse occurs upon cessation of TKI treatment due to the survival of a population of quiescent LSCs which possess BCR-ABL independent survival pathways, rendering this subset of LSCs immune to TKI-induced apoptosis. Even though the initial oncogenic impetus for the development of CML is the acquisition of the Ph, BCR-ABL signalling is not the sole pathway responsible for the persistence of LSCs post-transformation. BCR-ABL independent survival of LSCs is associated with a number of cellular changes, such as aberrant signalling though NF-kB and Beta-catenin, and deregulation of mitochondrial function relating to central carbon metabolism, oxidative phosphorylation and autophagy. The importance of this mitochondrial dysfunction for the survival of LSCs has been demonstrated by the selective eradication of CML LSCs both in vitro and in a xenotransplantation model of human CML using imatinib and tigecycline, an antibiotic which inhibits mitochondrial protein translation. This project therefore aims to further characterize the aberrant metabolic function exhibited by TKI resistant LSCs, and to use this increased resolution to identify and validate targets which can be used to selectively eliminate LSC populations.

慢性粒细胞白血病(CML)是一种由少量致癌白血病干细胞(LSCs)和多种成熟祖细胞组成的骨髓增生性疾病。LSCs是分化层级的顶端，负责原始细胞的聚集和驱动血液学复发。慢性粒细胞白血病的发展始于在一个单一的多能造血干细胞(HSC)中获得费城染色体(Ph)。Ph是9号和22号染色体的融合，导致了bcr-abl的形成，bcr-abl是导致HSC转化的嵌合原癌基因。BCR-ABL是一种固有活性的酪氨酸激酶(TK)，它的活性干扰和增强了JAK/STAT、PI3K/AKT和RAS/MEK等与癌症信号转导相关的通路。CML的治疗前景主要是由酪氨酸激酶抑制剂(TKIs)主导的，它阻断了BCR-ABL和ATP之间的相互作用，从而取消了下游信号通路。第一个以这种方式治疗CML的TKI是伊马替尼，在20世纪90年代末开发和试验，直到今天它仍然是一种标准治疗方法。大多数慢性期接受伊马替尼治疗的患者对治疗反应强烈，bcr-abl转录本大幅减少，有可能达到无法检测到的水平。O‘Brien等人2003年的一项研究表明，在伊马替尼治疗18个月后，87.1%的患者表现出主要的细胞遗传学反应，而76.2%的患者表现出完全的细胞遗传学反应。尽管患者对TKI治疗表现出良好的反应，但停止伊马替尼治疗后经常会出现细胞遗传学和血液学复发，这表明抑制bcr-abl本身并不是一种根治方法。大多数CML患者需要终生接受TKI治疗以防止复发，考虑到第二代TKI引起的血管并发症和继发耐药的可能性，这远远不是理想的。假设在停止TKI治疗后复发发生，这是由于具有BCR-ABL独立生存途径的一群静止的LSCs存活，使这一亚群的LSCs对TKI诱导的细胞凋亡具有免疫力。尽管CML发生的最初致癌动力是Ph的获得，但BCR-ABL信号并不是LSCs转化后持续存在的唯一途径。LSCs的bcr-abl非依赖性存活与一系列细胞变化有关，如通过核因子-kB和β-连环蛋白的信号异常，以及与中枢碳代谢、氧化磷酸化和自噬相关的线粒体功能的紊乱。使用伊马替尼和替吉环素(一种抑制线粒体蛋白翻译的抗生素)在体外和人CML异种移植模型中选择性地根除CML LSCs，证明了这种线粒体功能障碍对LSCs生存的重要性。因此，本项目旨在进一步表征耐TKI的LSC表现出的异常代谢功能，并利用这一提高的分辨率来识别和验证可用于选择性消除LSC群体的靶点。