Molecular and Cellular Basis of Clonal Dominance in Myeloid Malignancy

人类每天产生大约1000亿个新的血细胞来维持生存。在这个复杂的过程中偶尔会出现错误，这可能导致血癌，包括急性髓性白血病（AML）。AML是成年人中最常见的侵袭性血癌，在英国每年有3000例新病例，不幸的是，大多数人仍然在诊断后6个月内死于这种疾病。为了改善这些患者的预后，需要更好地了解这种疾病的生物学特性。AML是由于控制血液生成的基因出现多次错误或突变而引起的。随着时间的推移，这些突变通常在一小群血液干细胞/祖细胞（产生我们所需的所有血细胞的细胞）中逐步发生。最近发现，其中一些突变通常存在于尚未患血癌的健康老年人的血细胞中。这些突变似乎使细胞比正常情况下生长得更多，因此随着时间的推移，它们主宰了骨髓（血液产生的地方），并增加了未来患血癌的风险。这些突变中最常见的发生在控制DNA上“表观遗传”标记的基因上。表观遗传标记不影响DNA序列，但可以导致疾病，因为它们控制着基因的开启和关闭方式。在这个项目中，我们正在研究这些表观遗传调控因子的突变如何将正常的血液干细胞转变为异常的“白血病前期”细胞，进而导致AML。我们的目标是找出哪些血细胞发生突变，以及这些细胞中的哪些途径使它们异常生长。为此，我们将研究来自健康人类志愿者的血细胞，这些志愿者在髋关节或膝关节手术中捐献了骨髓样本，来自AML患者和具有其中一种突变的小鼠。我们的实验将帮助我们弄清楚突变如何改变细胞的行为方式，以及哪些基因被异常地打开和关闭。然后，我们将利用这些知识试图找到一种可以阻断的途径来阻止细胞生长。这项研究之所以重要，有两个原因。首先，它将使我们更好地了解AML和其他血癌的发展过程。其次，我们希望它能找到一种杀死白血病前细胞的方法，在白血病完全发展之前预防白血病，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 mistakes, 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 cancers 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 "preleukaemic" cells that can go on to cause AML. We aim to find out which blood cells get the mutations and which 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 change the way cells behave and what genes are 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 preleukaemic cells to prevent leukaemia before it fully develops, and to improve treatment for patients with AML.