Establishing the mechanism for RUVBL2 essentiality in acute myeloid leukaemia

尽管儿童常见白血病的治疗取得了显著进展，但某些类型的疾病，如急性髓系白血病(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为AML的儿童，以及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。白血病研究中的普遍共识是，可能导致这种新疗法的进展依赖于对疾病分子基础的更多了解。我们的研究小组研究了癌症基因如何劫持正常的细胞途径，以促进正常血细胞转化为白血病。我们和其他人已经证明，c-myb分子在大多数AML类型中介导癌症基因功能，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，这会导致正常血细胞被不起作用的白血病细胞取代，导致组织氧输送的灾难性缺陷，血液凝结不良，并容易受到感染。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。我们最近发现了一条在AML细胞中工作的途径，其中蛋白质RUVBL2控制c-myb的活性，确保它阻止AML细胞的分化。抑制RUVBL2虽然导致AML细胞死亡，但对正常血细胞发育影响不大。这表明，针对这种蛋白质的治疗可能是有效的，而且相对无毒。这个项目旨在描述RUVBL2如何控制c-myb，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AML疾病的实验模型来检验RUVBL2对c-myb功能控制的干扰对AML细胞的影响。我们将使用这个项目的结果来确定阻断RUVBL2功能的新疗法可能有多有效，并设想将这些信息用于AML这些疗法的未来开发。

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.