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

新型突变异柠檬酸脱氢酶抑制剂在急性髓系白血病中的作用表观基因组机制

• 批准号: MR/R007608/1
• 负责人: Lynn Swun Quek
• 金额: $ 162.32万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FR007608%2F1
• 关键词: Epigenomic; Mechanisms; Action; Novel; Mutant

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.

急性髓性白血病（AML）是成人中最常见的侵袭性白血病，大多数患者无法治愈。在AML中，基因突变导致骨髓中的未成熟细胞停止制造成熟细胞（分化阻滞和骨髓衰竭），并增加患者骨髓中的数量（扩增）。患者出现贫血、出血和感染症状，如不治疗则会导致死亡。AML的最有效的治疗方法是使用杀死白血病细胞的化疗药物。这些都是高毒性的，因为它们也会伤害体内的其他细胞。大多数AML患者是老年人，无法耐受这些类型的治疗。因此，我们需要有更有效，毒性更小的治疗，以恢复血液和骨髓功能（疾病缓解），以提高治愈率，延长患者生存期，提高生活质量。20%的AML患者有突变的基因编码的酶异柠檬酸脱氢酶1或2（IDH 1/2）。突变酶（mIDH）产生异常化学物质（或代谢物）右旋-2-羟基戊二酸（d2 HG）。这种代谢物已知会导致癌症（包括AML和脑肿瘤），最有可能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。这通过减少输血需求和感染风险使患者受益。不幸的是，大多数最初对mIDHi有反应的患者会产生耐药性和复发。我们不明白为什么会发生这种情况，或者为什么有些患者对mIDHi没有反应。我们也不完全了解mIDHi是如何工作的，但它很可能涉及基因控制机制的改变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。我的建议的目的是1）研究血细胞如何在正常骨髓中分化和成熟，以及这种分化和成熟过程在AML中是如何出错的（即分化阻断）2）研究mIDHi等药物如何能够重新编程AML细胞，使其分化为功能性成熟细胞3）在mIDHi无效的患者中，或者当患者的疾病对mIDHi产生耐药性时，找出AML细胞保留或被阻断的原因。如果我能发现我们如何靶向这些阻断的通路，例如，通过使用新药或通过将mIDHi的作用与其他药物结合，那么这可能对治疗患者有用。我将用于研究AML细胞行为的方法包括使用基因测序技术来观察基因在细胞中的表达，以及控制基因表达的机制（表观基因组学）。这可以提供对AML细胞更好的表征和理解，并用于确定AML患者是否更有可能或更少地对特定治疗作出反应。这可以帮助临床医生决定哪种治疗方法最适合个体患者，并帮助开发更有可能对个体有效的治疗组合。

项目成果

Clonal heterogeneity of acute myeloid leukemia treated with the IDH2 inhibitor enasidenib.

• DOI: 10.1038/s41591-018-0115-6
• 发表时间: 2018-08
• 期刊: Nature medicine
• 影响因子: 82.9
• 作者: Quek L;David MD;Kennedy A;Metzner M;Amatangelo M;Shih A;Stoilova B;Quivoron C;Heiblig M;Willekens C;Saada V;Alsafadi S;Vijayabaskar MS;Peniket A;Bernard OA;Agresta S;Yen K;MacBeth K;Stein E;Vassiliou GS;Levine R;De Botton S;Thakurta A;Penard-Lacronique V;Vyas P
• 通讯作者: Vyas P