Establishing the mechanism for RUVBL2 essentiality in acute myeloid leukaemia

建立 RUVBL2 在急性髓系白血病中的重要性机制

• 批准号: MR/S021000/1
• 负责人: Owen Williams
• 金额: $ 58.08万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FS021000%2F1
• 关键词: Establishing; mechanism; RUVBL2; essentiality; acute

Despite remarkable advances in the treatment of common leukaemia in children, some types of this disease, such as acute myeloid leukaemia (AML), are still difficult to treat. Current therapy fails to cure 1 in 3 children diagnosed with AML, and over half of adult patients, indicating an urgent need for new and improved treatments. There is general consensus in leukaemia research that advances likely to result in such new therapies rely on achieving a greater understanding of the molecular basis of the disease. Our group studies how cancer genes hijack normal cellular pathways to promote conversion of normal blood cells into leukaemia. We and others have shown that the molecule c-MYB mediates cancer gene function in most AML types, ensuring that AML cells continuously divide, producing copies of themselves, and that they do not differentiate into mature blood cells. In AML patients, this results in the replacement of normal blood cells with non-functional leukaemia cells, leading to catastrophic deficiencies in tissue oxygen delivery, poor blood clotting and susceptibility to infection. However, targeting c-MYB itself is problematical, mainly due to its requirement for normal blood cell development. We recently uncovered a pathway operating in AML cells, in which the protein RUVBL2 controls the activity of c-MYB, ensuring it blocks differentiation of AML cells. Although inhibition of RUVBL2 resulted in the death of AML cells, it had little impact on normal blood cell development. This suggests that therapies targeting this protein may be effective and relatively non-toxic. This project aims to characterise how RUVBL2 controls c-MYB and to discover what parts of RUVBL2 are necessary for this control. We will then examine the effects of interfering with control of c-MYB function by RUVBL2 on AML cells using experimental models of the disease. We will use the results from this project to determine how effective new therapies that block RUVBL2 function are likely to be and envisage using this information for future development of these therapies in AML.

尽管在治疗儿童普通白血病方面取得了显著进展，但某些类型的这种疾病，如急性髓性白血病（AML），仍然难以治疗。目前的治疗方法无法治愈三分之一被诊断患有AML的儿童和超过一半的成人患者，这表明迫切需要新的和改进的治疗方法。在白血病研究中有一个普遍的共识，即可能导致这种新疗法的进展依赖于对这种疾病的分子基础有更深入的了解。我们小组研究癌症基因如何劫持正常细胞通路，促进正常血细胞转化为白血病。我们和其他人已经证明，在大多数AML类型中，分子c-MYB介导癌症基因功能，确保AML细胞持续分裂，产生自身的副本，并且它们不会分化为成熟的血细胞。在AML患者中，这导致正常血细胞被非功能性白血病细胞取代，导致组织氧输送的灾难性缺陷，血液凝固不良和易感染。然而，靶向c-MYB本身是有问题的，主要是因为它需要正常的血细胞发育。我们最近发现了一个在AML细胞中运作的途径，其中RUVBL2蛋白控制c-MYB的活性，确保它阻断AML细胞的分化。虽然抑制RUVBL2可导致AML细胞死亡，但对正常血细胞发育影响不大。这表明针对该蛋白的治疗可能有效且相对无毒。这个项目旨在描述RUVBL2是如何控制c-MYB的，并发现RUVBL2的哪些部分是这种控制所必需的。然后，我们将使用该疾病的实验模型检查RUVBL2干扰c-MYB功能控制对AML细胞的影响。我们将利用该项目的结果来确定阻断RUVBL2功能的新疗法的有效性，并设想将这些信息用于AML中这些疗法的未来开发。

项目成果

Direct targeted therapy for MLL-fusion-driven high-risk acute leukaemias.

• DOI: 10.1002/ctm2.933
• 发表时间: 2022-06
• 期刊: Clinical and translational medicine
• 影响因子: 10.6

Identification of a c-MYB-directed therapeutic for acute myeloid leukemia.

• DOI: 10.1038/s41375-022-01554-9
• 发表时间: 2022-06
• 期刊: LEUKEMIA
• 影响因子: 11.4
• 作者: Clesham, Katherine;Walf-Vorderwulbecke, Vanessa;Gasparoli, Luca;Virely, Clemence;Cantilena, Sandra;Tsakaneli, Alexia;Inglott, Sarah;Adams, Stuart;Samarasinghe, Sujith;Bartram, Jack;Williams, Gareth;de Boer, Jasper;Williams, Owen
• 通讯作者: Williams, Owen

Drug Repurposing for Targeting Acute Leukemia With KMT2A (MLL)-Gene Rearrangements.

• DOI: 10.3389/fphar.2021.741413
• 发表时间: 2021
• 期刊: Frontiers in pharmacology
• 影响因子: 5.6
• 作者: Tsakaneli A;Williams O
• 通讯作者: Williams O