Molecular basis for clonal advantage in myeloid blood cancers

为了生存，人类每天产生大约1000亿个新的血细胞。在这个复杂的过程中偶尔会出现错误，这可能会导致血癌，包括急性髓系白血病(AML)。急性髓细胞白血病是最常见的成人侵袭性血癌，在英国每年新增3000例，不幸的是，大多数人仍然在确诊后6个月内死于这种疾病。需要更好地了解这种疾病的生物学，以改善这些患者的预后。急性髓系白血病是由于控制血液生产的基因发生多重改变或突变而产生的。随着时间的推移，这些突变通常以一种循序渐进的方式发生在一小群血干/祖细胞中(这些细胞产生了我们需要的所有血细胞)。最近发现，这些突变中的一些通常在尚未患血癌的健康老年人的血细胞中发现。这些突变似乎使细胞比正常情况下生长得更快，因此随着时间的推移，它们主导了骨髓(生产血液的地方)，并增加了未来发展为血癌的风险。其中最常见的突变发生在控制DNA上的“表观遗传”标记的基因中。表观遗传标记不会影响DNA序列，但可能会导致疾病，因为它们控制着基因的开启和关闭。在这个项目中，我们正在研究这些表观遗传调节因子的突变如何将正常的血液干细胞转变为异常的“白血病前”细胞，从而可能继续导致AML。我们的目标是找出哪些血细胞获得了突变，以及这些细胞中的哪些途径使它们异常生长。为此，我们将研究健康人类志愿者的血细胞，这些志愿者捐赠了在髋关节或膝盖手术中获得的骨髓样本，来自AML患者和带有其中一种突变的小鼠。我们的实验将帮助我们找出突变是如何使细胞行为异常的，以及哪些基因被异常地开启和关闭。然后，我们将利用这些知识，试图找到一条可以被阻断的途径，以阻止细胞生长。这项研究之所以重要，有两个原因。首先，它将让我们更好地了解AML和其他血癌是如何发展的。其次，我们希望它能找到一种方法，在白血病完全发展之前杀死白血病前期细胞，以预防白血病，并改善AML患者的治疗。

Humans produce around 100 billion new blood cells daily to survive. Occasionally mistakes occur in this complex process, which may lead to blood cancer, including acute myeloid leukaemia (AML). AML is the most common aggressive blood cancer in adults with 3000 new cases per year in the UK, and unfortunately the majority still die of their disease within 6 months of diagnosis. A better understanding of the biology of the disease is needed to improve the outcome for these patients. AML arises as a result of multiple alterations, or mutations, in genes that control blood production. These mutations usually occur in a step-wise manner over time in a small pool of blood stem/progenitor cells (the cells that give rise to all the blood cells we need). Recently it was discovered that some of these mutations are commonly found in the blood cells of healthy older people who do not have yet have blood cancer. These mutations appear to make the cells grow more than is normal, so that over time they dominate the bone marrow (where blood is produced), and increase the risk of developing blood cancer in the future. The most common of these mutations occur in genes which control "epigenetic" marks on the DNA. Epigenetic marks do not affect the DNA sequence, but can contribute to disease as they control how genes are switched on and off. In this project, we are studying how mutations in these epigenetic regulators turn normal blood stem cells into abnormal "pre-leukaemic" cells that can go on to cause AML. We aim to find out which blood cells get the mutations and what pathways in these cells make them grow abnormally. To do this, we will be studying blood cells from healthy human volunteers who have donated bone marrow samples obtained during hip or knee operations, from patients with AML and in mice with one of the mutations. Our experiments will help us to work out how the mutations are making the cells behave abnormally and what genes are being switched on and off abnormally. We will then use this knowledge to try to find a pathway that can be blocked to stop the cells growing. This research is important for two reasons. Firstly, it will give us a better understanding of how AML and other blood cancers develop. Secondly, we hope that it will identify a way to kill the pre-leukaemic cells to prevent leukaemia before it fully develops, and to improve treatment for patients with AML.