The role of RUNX2 in MLL-AF9 acute myeloid leukaemia

RUNX2在MLL-AF9急性髓系白血病中的作用

• 批准号: MR/M003221/1
• 金额: $ 30.02万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FM003221%2F1
• 关键词: role; RUNX2; MLL; AF9; acute

Mixed lineage leukaemias are a subset of aggressive blood cancers. They are responsible for 15-20% of paediatric acute myeloid leukaemia (AML) and 5% of adult AML. Mixed lineage leukaemias in general have a dismal prognosis - as few as 14% of patients diagnosed with mixed lineage leukaemia AML are cured. This is in contrast to other types of childhood acute leukaemia where cure rates are as high as 90%. Mixed lineage leukaemias are caused by chromosomal rearrangements that result in the Mixed-Lineage Leukaemia (MLL) gene fusing abnormally with other genes. This rearrangement leads to the production of an aberrant fusion protein (MLL-FP) that is thought to drive the leukaemia by activating target genes that would not normally be expressed.A potentially exciting approach to treating resistant cancers such as mixed lineage leukaemias, is the development of small molecule inhibitors that specifically target aberrant processes in cancer cells but leave normal cells unharmed. In order to be successful, such an approach requires highly detailed information about cellular processes in cancer cells on the molecular level. Thus, there are at least two reasons why research into MLL-FP AML is important. Firstly, we need to improve treatment of this subset of acute leukaemias. Secondly, in order to do so, we need to understand molecular mechanisms specific to MLL-FP AML and in the process, discover information about key pathways that may be applicable to leukaemia in general.In this project, we will use several strategies to understand the role of MLL-FP target genes that have previously been identified. We will use technology such as "RNA interference" and "genetic engineering" to specifically inhibit the expression of our genes of interest in MLL-FP leukaemia cells. We will then examine the effect of such inhibition on leukaemia survival. We also aim to identify the changes in downstream gene expression when our target genes are inhibited. We believe this strategy will elucidate the requirement and function of our genes of interest and may identify specific pathways amenable to therapeutic intervention.The work will be part of a PhD project conducted in the MRC supported Weatherall Institute of Molecular Medicine, University of Oxford, principally conducted by a Haematology specialty doctor training to be an academic clinician, and specialising in the care of this group of patients.

混合谱系白血病是侵袭性血癌的一个子集。他们负责15-20%的儿童急性髓性白血病（AML）和5%的成人AML。混合谱系白血病通常预后不良-只有14%的诊断为混合谱系白血病AML的患者治愈。这与其他类型的儿童急性白血病形成鲜明对比，后者的治愈率高达90%。混合谱系白血病是由染色体重排引起的，导致混合谱系白血病（MLL）基因与其他基因异常融合。这种重排导致异常融合蛋白（MLL-FP）的产生，该异常融合蛋白被认为通过激活通常不会表达的靶基因来驱动白血病。一种潜在的令人兴奋的治疗耐药癌症（如混合谱系白血病）的方法是开发特异性靶向癌细胞中的异常过程但不伤害正常细胞的小分子抑制剂。为了取得成功，这种方法需要在分子水平上获得关于癌细胞中细胞过程的非常详细的信息。因此，对MLL-FP AML的研究之所以重要，至少有两个原因。首先，我们需要改善对这类急性白血病的治疗。其次，为了做到这一点，我们需要了解特定于MLL-FP AML的分子机制，并在此过程中发现可能适用于白血病的关键途径的信息。在本项目中，我们将使用几种策略来了解以前已确定的MLL-FP靶基因的作用。我们将使用“RNA干扰”和“基因工程”等技术来特异性抑制MLL-FP白血病细胞中我们感兴趣的基因的表达。然后，我们将研究这种抑制对白血病生存的影响。我们还旨在确定当我们的靶基因被抑制时下游基因表达的变化。我们相信这一策略将阐明我们感兴趣的基因的需求和功能，并可能确定适合治疗干预的特定途径。这项工作将是在MRC支持的牛津大学Weatherall分子医学研究所进行的博士项目的一部分，主要由血液学专业医生进行培训，成为一名学术临床医生，专门负责这类患者的护理。

项目成果

H3K79me2/3 controls enhancer-promoter interactions and activation of the pan-cancer stem cell marker PROM1/CD133 in MLL-AF4 leukemia cells.

• DOI: 10.1038/s41375-020-0808-y
• 发表时间: 2021-01
• 期刊: Leukemia
• 影响因子: 11.4
• 作者: Godfrey L;Crump NT;O'Byrne S;Lau IJ;Rice S;Harman JR;Jackson T;Elliott N;Buck G;Connor C;Thorne R;Knapp DJHF;Heidenreich O;Vyas P;Menendez P;Inglott S;Ancliff P;Geng H;Roberts I;Roy A;Milne TA
• 通讯作者: Milne TA

Functional and Genetic Heterogeneity of Distinct Leukemic Stem Cell Populations in CD34-Human Acute Myeloid Leukemia

CD34-人急性髓系白血病中不同白血病干细胞群的功能和遗传异质性

• 发表时间: 2014
• 期刊: BLOOD
• 影响因子: 20.3
• 作者: Quek Lynn

DOT1L inhibition reveals a distinct class of enhancers dependent on H3K79 methylation

DOT1L 抑制揭示了一类依赖于 H3K79 甲基化的独特增强子

• DOI: 10.1101/383489
• 发表时间: 2018
• 作者: Godfrey L

Double Relapsed and/or Refractory Multiple Myeloma: Clinical Outcomes and Real World Healthcare Costs.

• DOI: 10.1371/journal.pone.0136207
• 发表时间: 2015
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Gooding S;Lau IJ;Sheikh M;Roberts P;Wong J;Dickens E;Bullement A;Elvidge J;Lee D;Ramasamy K
• 通讯作者: Ramasamy K