The differential role of PU.1 in normal and malignant haematopoiesis: from master regulator of differentiation to coordinator of leukaemia networks

PU.1在正常和恶性造血中的不同作用：从分化的主调节因子到白血病网络的协调员

基本信息

批准号：
MR/X008371/1
负责人：
Brian Huntly
金额：
$ 100.81万
依托单位：
University of Cambridge
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2023
资助国家：
英国
起止时间：
2023 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FX008371%2F1
关键词：
differential role PU.1 normal malignant

项目摘要

The behaviour of cells is determined by the proteins that they contain. This protein composition greatly differs between cell types and even between cells within tissues and explains the different cell behaviours and functions that we observe. The levels of these proteins and why different proteins are present in specific cells are determined by tightly-regulated processes called transcription, where an intermediate product called a transcript is generated from a gene's DNA-template, and translation, where the transcript is then used to assemble the specific protein coded for by that gene. The process of transcription has been well studied in blood formation. Blood is a very complex tissue, containing different specialised cells that carry oxygen, cells that cause the blood to clot and cells that fight infection. However, every cell within the blood is generated from a single source: the haematopoietic stem cell (HSC), with the differing cells maturing and becoming more specialised through an ordered process called differentiation. In general, differentiation is orchestrated by specialised proteins called transcription factors that bind to and regulate the DNA of specific genes whose protein products are necessary for specialisation. The binding of the transcription factors then instruct the generation of transcripts from that gene, resulting in protein expression. The expression of these transcription factors is also tightly controlled and changes through differentiation and specialisation.One of the cardinal features of leukaemias, and most cancers, is that this ordered process of differentiation is blocked and in effect, no specialised mature blood cells are formed. Acute leukaemias, such as Acute Myeloid Leukaemia (AML), are aggressive cancers with a dismal survival rate and are thus an unmet medical need. We have recently discovered that a transcription factor called PU.1 that is usually associated with normal blood differentiation is also absolutely required to maintain AML, a cellular state that lacks differentiation. This project will focus on answering the interesting question of why PU.1 drives differentiation in normal cells yet maintains AML. This seems at first-glance counterintuitive, however we speculate that: 1) differences in levels of the PU.1 protein, 2) differences in its binding to and regulation of different target genes and 3) differences in the proteins that it interacts with and alterations in its structure (called post-translational modifications) between the normal and leukaemia state explain this altered behaviour. We will interrogate these avenues in this proposal, utilising state-of-the-art techniques in relevant model systems and multiple AML patient samples. Moreover, we will target PU.1 and its interaction partners with specific drugs and genetic perturbations to determine if it may be a relevant and safe therapeutic target in patients with AML. Therefore, the likely outcomes of this project are that we will significantly improve our understanding both of leukaemia biology and of the normal differentiation of blood cells, that we will identify PU.1 and its interacting proteins as potential therapeutic targets in AML and potentially that we may suggest an effective therapy in this aggressive disease.

细胞的行为是由它们所含的蛋白质决定的。这种蛋白质组成在细胞类型之间甚至组织内的细胞之间存在很大差异，并解释了我们观察到的不同细胞行为和功能。这些蛋白质的水平以及为什么不同的蛋白质存在于特定细胞中，是由严格调控的转录过程决定的，在转录过程中，从基因的 DNA 模板中生成称为转录本的中间产物，然后在翻译过程中，转录本被用于组装该基因编码的特定蛋白质。转录过程在血液形成中已得到充分研究。血液是一种非常复杂的组织，包含不同的携带氧气的特殊细胞、导致血液凝结的细胞和抵抗感染的细胞。然而，血液中的每个细胞都是由单一来源产生的：造血干细胞（HSC），不同的细胞通过称为分化的有序过程成熟并变得更加特化。一般来说，分化是由称为转录因子的特殊蛋白质精心策划的，这些蛋白质结合并调节特定基因的 DNA，而这些基因的蛋白质产物是专门化所必需的。然后转录因子的结合指导该基因生成转录本，从而导致蛋白质表达。这些转录因子的表达也受到严格控制，并通过分化和特化而发生变化。白血病和大多数癌症的主要特征之一是这种有序的分化过程被阻断，实际上不会形成特化的成熟血细胞。急性白血病，例如急性髓性白血病（AML），是一种侵袭性癌症，存活率很低，因此是一种未得到满足的医疗需求。我们最近发现，通常与正常血液分化相关的一种称为 PU.1 的转录因子对于维持 AML（一种缺乏分化的细胞状态）也是绝对必需的。该项目将重点回答为什么 PU.1 驱动正常细胞分化但维持 AML 的有趣问题。乍一看这似乎违反直觉，但我们推测：1) PU.1 蛋白水平的差异，2) 它与不同靶基因的结合和调节的差异，以及 3) 与其相互作用的蛋白质的差异正常状态和白血病状态之间的结构变化（称为翻译后修饰）解释了这种行为改变。我们将在本提案中探讨这些途径，利用相关模型系统和多个 AML 患者样本中的最先进技术。此外，我们将针对 PU.1 及其与特定药物和基因扰动的相互作用伙伴，以确定它是否可能是 AML 患者的相关且安全的治疗靶点。因此，该项目的可能结果是，我们将显着提高对白血病生物学和血细胞正常分化的理解，我们将确定 PU.1 及其相互作用蛋白作为 AML 的潜在治疗靶点，并且我们有可能可能会建议针对这种侵袭性疾病的有效治疗方法。