Epigenomic Mechanisms of Action of Novel Mutant Isocitrate Dehydrogenase Inhibitors in Acute Myeloid Leukaemia

急性髓系白血病(AML)是成人最常见的侵袭性白血病，在大多数患者中是无法治愈的。在AML中，基因突变导致骨髓中的未成熟细胞停止生成成熟细胞(分化障碍和骨髓衰竭)，并增加患者骨髓中的IS数量(扩张)。患者出现贫血、出血和感染的症状，导致死亡而得不到治疗。AML最有效的治疗方法是使用能杀死白血病细胞的化疗药物。这些都是剧毒的，因为它们还会伤害身体中的其他细胞。大多数AML患者是老年人，无法耐受这些类型的治疗。因此，我们需要更有效、毒性更低的治疗方法来恢复血液和骨髓功能(疾病缓解)，以提高治愈率、延长患者生存时间、改善生活质量。20%的AML患者存在编码异柠檬酸脱氢酶1或2(IDH1/2)的基因突变。突变酶(MIDH)产生一种异常的化学物质(或代谢物)--右旋-2-羟基戊二酸(D2HG)。已知这种代谢物会导致癌症(包括AML和脑瘤)，最有可能的是通过阻止细胞正常成熟。抑制MIDH(MIDHi)的新药对约40%的异柠檬酸脱氢酶突变(IDHm)AML患者有效。它的工作原理是通过使未成熟的AML细胞成为有用的成熟血细胞来减少它们的数量。这使患者受益，因为它减少了输血需求和感染风险。不幸的是，大多数最初对mIDHi有反应的患者会产生耐药性并复发。我们不明白为什么会发生这种情况，或者为什么一些患者对mIDHi没有反应。我们也不完全了解mIDHi是如何工作的，但它可能涉及基因控制机制的变化为了解决这些基本问题，我想了解通常在血细胞成熟时表达的基因的控制机制中出了什么问题，以及这是如何导致AML的。我建议的目的是1)研究正常骨髓中血细胞如何分化和成熟，以及这一分化和成熟过程在AML中如何出错(即分化阻断)2)研究像mIDHi这样的药物如何能够重新编程AML细胞，使其分化为有功能的成熟细胞3)在mIDHi无效或患者的疾病对mIDHi产生抗药性的患者中，了解AML细胞为何残留或被阻断。如果我能发现我们如何针对这些被阻断的途径，例如，通过使用新药或通过将mIDHi的效果与其他药物结合起来，那么这可能对治疗患者有用。我将使用的方法来研究AML细胞的行为，包括使用基因测序技术来查看基因在细胞中的表达方式，以及控制基因表达的机制(表观基因组学)。这可以更好地描述和理解AML细胞，并用于确定AML患者对特定治疗的反应是更大还是更小。这可以帮助临床医生决定哪些治疗方法对个别患者最好，并帮助开发更有可能对个别患者有效的治疗组合。

Acute myeloid leukaemia (AML) is a most common aggressive leukaemia in adults and is incurable in most patients. In AML, gene mutations cause immature cells in bone marrow to stop making mature cells (differentiation block and bone marrow failure) and to increase is numbers in patient bone marrow (expansion). Patients develop symptoms of anaemia, bleeding and infections, which lead to death is untreated. Most effective treatments for AML use chemotherapy drugs which kill leukaemic cells. These are highly toxic as they also harm other cells in the body. The majority of patients with AML are elderly and unable to tolerate these types of treatment. We therefore need to have more effective, less toxic treatments to restore blood and bone marrow function (disease remission) to both improve rates of cure, prolong patient survival, improve quality of life.20% of AML patients have a mutation in genes coding for the enzymes isocitrate dehydrogenase 1 or 2 (IDH1/2). The mutant enzyme (mIDH) produces an abnormal chemical (or metabolite), dextro-2-hydroxyglutarate (d2HG). This metabolite is known to cause cancer (including AML and brain tumours), most probably by stopping cells from maturing properly.New drugs which inhibit mIDH (mIDHi), is effective for ~40% of Isocitrate Dehydrogenase mutant (IDHm) AML patients. It works by reducing the number of immature AML cells by causing them to become useful mature blood cells. This benefits patients by reducing the need for blood transfusions and infection risk. Unfortunately, most patients who initially respond to mIDHi will develop resistance and relapse. We do not understand why this happens, or why some patients never respond to mIDHi. We also do not fully understand how mIDHi work, but it is likely to involve changes to the control mechanisms of genesTo address these fundamental questions, I want to understand what goes wrong in the control mechanism of genes which are usually expressed when blood cells mature, and how this causes AML. The aims of my proposal is to1) Study how blood cells differentiate and mature in normal bone marrow and how this process of differentiation and maturation goes wrong in AML (i.e. differentiation block)2) Investigate how drugs like mIDHi are able to re-programme AML cells to make them differentiate into functional mature cells 3) In patients where mIDHi are not effective, or when a patient's disease becomes resistant to mIDHi, find out why AML cells remain, or become blocked. If I can discover how we can target these blocked pathways, for example, by using novel drugs or by combining the effects of mIDHi with other drugs, then this could be useful for treating patients.The methods I will use to study the behaviour of AML cells include using genetic sequencing techniques to look at how genes are expressed in cells, and also what the mechanisms are which control gene expression (epigenomics). This could provide a better characterisation and understanding of AML cells and be used to determine if AML patients are more or less likely to respond to a particular treatment. This can help clinicians to decide which treatments are best for an individual patient, and help develop combinations of treatments which are more likely to work for an individual.