Molecular and Cellular Basis of Clonal Dominance in Myeloid Malignancy

骨髓恶性肿瘤克隆优势的分子和细胞基础

• 批准号: MR/R002258/1
• 负责人: Niels Jakobsen
• 金额: $ 37.87万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FR002258%2F1
• 关键词: Molecular; Cellular; Basis; Clonal; Dominance

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.

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。为了改善这些患者的预后，需要对这种疾病的生物学有更好的了解。AML是由于控制血液产生的基因的多个错误或突变而产生的。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)，并增加了未来患血癌的风险。这些突变中最常见的发生在控制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“白血病前期”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，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，这些志愿者捐赠了髋关节或膝盖手术期间获得的骨髓样本，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弄清楚这些突变如何改变细胞的行为方式，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以阻止细胞生长的途径。这项研究之所以重要，原因有两个。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。

项目成果

A Randomized Comparison of the Fractionated Versus Single Dose Schedule of Gemtuzumab Ozogamicin at Induction with Determinants of Benefit for Older AML Patients: UK NCRI AML18 Trial Results

诱导时吉妥珠单抗奥佐米星分次给药方案与单剂量方案的随机比较以及老年 AML 患者获益的决定因素：英国 NCRI AML18 试验结果

• DOI: 10.1182/blood-2022-162245
• 发表时间: 2022
• 期刊: Blood
• 影响因子: 20.3
• 作者: Freeman S

Identification and Age-dependent Increase of Platelet Biased Human Hematopoietic Stem Cells

• DOI: 10.1101/2022.01.14.475546
• 发表时间: 2022-01
• 期刊: bioRxiv
• 作者: Merve Aksöz;Grigore-Aristide Gafencu;B. Stoilova;M. Buono;Yiran Meng;N. A. Jakobsen;M. Metzner;Sally-Ann Clark;R. Beveridge;S. Thongjuea;P. Vyas;C. Nerlov

Dynamics of Clonal Hematopoiesis Inferred By Modelling Deep Bulk Whole-Genome Sequencing Data at a Single Time Point

通过对单个时间点的深度批量全基因组测序数据进行建模来推断克隆造血的动态

• DOI: 10.1182/blood-2022-166236
• 发表时间: 2022
• 期刊: Blood
• 影响因子: 20.3
• 作者: Ansari-Pour N

Single-Cell Analysis of Human Clonal Hematopoiesis Identifies Distinct Impact of DNMT3A and TET2 mutations on Hematopoietic Differentiation

人类克隆造血的单细胞分析确定了 DNMT3A 和 TET2 突变对造血分化的不同影响

• DOI: 10.1182/blood-2022-166474
• 发表时间: 2022
• 期刊: Blood
• 影响因子: 20.3
• 作者: Jakobsen N

Characterising the cellular and molecular basis of age-related clonal haematopoiesis

表征与年龄相关的克隆造血的细胞和分子基础

• 发表时间: 2022
• 作者: Jakobsen Niels Asger