The role of the bone marrow niche in the maintenance of cancer stem cells in chronic myeloid leukaemia (CML)

骨髓生态位在维持慢性粒细胞白血病（CML）癌症干细胞中的作用

• 批准号: 1938281
• 金额: --
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-1938281
• 关键词: role; bone; marrow; niche; maintenance

Developing cancer therapies that eradicate cancer stem cells (CSC) and cure the disease is hugely challenging. This is exemplified in chronic myeloid leukaemia (CML), an advanced paradigm of CSC research, where BCR-ABL1 transforms a normal haemopoietic stem cell (HSC) into a leukaemic stem cell (LSC). Most CML patients present in chronic phase (CP), during which BCR-ABL1 drives molecular changes in the LSC that may increase their "fitness" and drive their clonal expansion according to Darwinian principles. In worse case scenarios, these changes result in total resistance to standard-of-care tyrosine kinase inhibitors (TKI) and promotes disease progression to accelerated phase and then to terminal blast phase. The key bottleneck to curing CML is the sub-population(s) of LSC in the bone marrow (BM) that persists throughout TKI treatment, it is these populations in which drug resistance and disease progression occur. TKI-resistant LSCs sustain residual CML in patients, drive TKI-resistance and disease progression through clonal evolution and allows for relapse upon TKI discontinuation.To date, our knowledge of LSC biology has been based on analysis of bulk cell populations taken from patient samples at diagnosis or relapse. However, for TKI-resistant LSC in patients on TKI, we know very little about the molecular mechanisms of how they evolve, what pathways they require, and how they vary among patients. This is because (1) the TKI-resistant LSC are extremely rare in the BM (particularly in MMR), and (2) to date, LSC cannot be selectively isolated from normal HSC that reconstitute normal haemopoiesis in the BM during TKI therapy. For these reasons, it is not surprising that, despite the identification of more than 40 drug targets in LSC over the last 15 years, relatively few drugs reach clinical trials, and none have replaced, or even supplemented TKI as the standard-of-care.Holyoake was the first to demonstrate that CML-CSCs are not oncogene-addicted. Since 2007, Holyoake, et al have compiled (LEUKomics, CML-specific domain within STEMFORMATICS, >30 in-house/public multi-omics datasets describing CML-CSCs. LSCs do not require BCR-ABL-kinase activity for survival, nor do they have BCR-ABL kinase domain mutations in patients during CP, inferring that they survive through BCR-ABL-kinase-independent pathways. Data-mining has revealed three key hubs (p53, c-Myc, PRC2) controlling a targetable CML-CSC intrinsic network. Demonstrating interactions between CML-CSC and their BM microenvironment, revealing cytokines/chemokines, JAK/STAT, N-cadherin/WNT/b-catenin and hedgehog signalling as potential key players.Using the murine stem cell leukaemia (SCL) gene 3' enhancer, transactivator protein (Tta), BCR-ABL (SCL-tTA-BCR-ABL) model we will be able to induce BCR-ABL expression via tetracycline withdrawal (driven off SCL promotion), which resembles chronic phase CML. Extending current collaborations to provide a comprehensive transcriptomic landscape of CML-CSC and key BM niche components that support CSC. My research will:1. Determine which niche cell subsets (mesenchymal stem cells (MSC) and macrophages) support CML-CSCs altering the disease kinetics of CML and TKI-response in a well-described CML transgenic (SCL-tTA-BCR-ABL) mouse model2. Determine whether CML-CSC are dependent (in terms of disease initiation, maintenance, response to therapy and relapse) on either MSC or macrophages within the BM/spleen niche. Positive findings would then be investigated in human CML samples and in the xenograft NSG model, using the CML biobank, the largest of its kind worldwide.

开发根除癌症干细胞（CSC）并治愈癌症的癌症疗法是一项巨大的挑战。慢性髓性白血病（CML）是CSC研究的一个先进范例，BCR-ABL1将正常造血干细胞（HSC）转化为白血病干细胞（LSC）。大多数CML患者处于慢性期（chronic phase， CP），在此期间，BCR-ABL1驱动LSC的分子变化，根据达尔文原理，这些变化可能会增加LSC的“适应度”并驱动它们的克隆扩增。在更糟糕的情况下，这些变化导致对标准护理酪氨酸激酶抑制剂（TKI）的完全耐药，并促进疾病进展到加速期，然后到终末blast期。治疗CML的关键瓶颈是在TKI治疗过程中持续存在的骨髓中LSC亚群，正是这些亚群发生耐药性和疾病进展。TKI耐药LSCs维持患者的残余CML，通过克隆进化驱动TKI耐药和疾病进展，并允许TKI停药后复发。迄今为止，我们对LSC生物学的了解是基于对诊断或复发时患者样本中采集的大块细胞群的分析。然而，对于TKI患者的TKI耐药LSC，我们对它们如何进化的分子机制知之甚少，它们需要什么途径，以及它们在患者之间如何变化。这是因为(1)TKI耐药LSC在骨髓中极为罕见（尤其是在MMR中），(2)迄今为止，LSC不能从TKI治疗期间重建骨髓正常造血的正常HSC中选择性分离出来。由于这些原因，不足为奇的是，尽管在过去的15年里，LSC中发现了40多种药物靶点，但进入临床试验的药物相对较少，而且没有一种药物取代甚至补充TKI作为标准治疗方法。Holyoake是第一个证明CML-CSCs不具有癌基因依赖性的人。自2007年以来，Holyoake等人在STEMFORMATICS中编制了（LEUKomics）， cml特定域，以及30个内部/公开的描述CML-CSCs的多组学数据集。LSCs不需要BCR-ABL激酶活性来存活，在CP患者中也没有BCR-ABL激酶结构域突变，推断它们通过BCR-ABL激酶非依赖性途径存活。数据挖掘揭示了三个关键枢纽（p53, c-Myc, PRC2）控制可靶向CML-CSC固有网络。证明CML-CSC与其BM微环境之间的相互作用，揭示细胞因子/趋化因子，JAK/STAT， N-cadherin/WNT/b-catenin和刺猬信号传导是潜在的关键参与者。利用小鼠干细胞白血病（SCL）基因3′增强子、反激活蛋白（Tta）、BCR-ABL （SCL- Tta -BCR-ABL）模型，我们将能够通过四环素戒断（驱动SCL促进）诱导BCR-ABL表达，这类似于慢性期CML。扩展目前的合作，提供CML-CSC和支持CSC的关键BM利基组件的全面转录组学景观。我的研究将：1。在一个描述良好的CML转基因（SCL-tTA-BCR-ABL）小鼠模型中，确定哪个生态位细胞亚群（间充质干细胞（MSC）和巨噬细胞）支持CML- cscs改变CML的疾病动力学和tki反应2。确定CML-CSC是否依赖于骨髓/脾脏生态位内的MSC或巨噬细胞（在疾病发生、维持、治疗反应和复发方面）。阳性结果将在人类CML样本和异种移植物NSG模型中进行研究，使用世界上最大的CML生物库。