Podcasts 科学播客 | 「唐氏综合征儿童更易患白血病：干细胞研究揭示端倪」

Ana Cvejic

Maybe something that is less well known, but something that that we were particularly interested in is that these children, they have 150-fold higher chance of developing leukaemia compared to the children that do not have trisomy of chromosome 21.

我们特别感兴趣而少有人知的一点是，与健康儿童相比，唐氏综合征患儿患白血病的风险高出150倍。

Benjamin Thompson

This is Ana Cvejic from the University of Copenhagen in Denmark, one of the authors of the paper. The risk of developing a type of leukaemia is hugely elevated for these children in the first five years of life and Ana and her colleagues have been working to figure out why this might be, building on the work of other teams.

这是该论文的作者之一，来自丹麦哥本哈根大学的Ana Cvejic。对于这些患儿来说，生命的前五年患白血病的风险大幅升高。安娜和她的同事们在其他研究团队工作的基础上，努力探究其中的原因。

Ana Cvejic

What we actually know now for a decades is that all of these events that we are seeing early in childhood in children with Down’s syndrome are actually having their beginnings during fetal development, which will later on in a certain sequence of events lead to development of the leukaemia.

数十年前我们就知道，唐氏综合征儿童在幼年时期出现的所有血液问题，实际上在胎儿发育期间就已开始。这些早期事件随后会按一定顺序发展，最终导致白血病的发生。

Benjamin Thompson

Previous research established that cells at the centre of this sequence are haematopoietic stem cells — which have the ability to divide and develop into the various types of blood cells, and established that certain genetic mutations played a key role. But Ana wanted to dig deeper into what’s going on in cells that have an extra copy of chromosome 21, and how this might lead to leukaemia and other blood-related issues. First, she and her colleagues took a snapshot of all the individual cells in fetal liver samples. Much of their work concentrated on the liver, as it’s one of the main places in a developing fetus where blood cells are produced. This cellular census matched what others had found.

先前的研究已证实，上述过程中核心的细胞是造血干细胞——它们能够分裂并发育成各种类型的血细胞，而其中某些基因突变起着关键作用。但安娜希望更深入了解在拥有额外一条21号染色体的细胞中发生了什么，以及这如何导致白血病和其他血液相关问题。首先，她和同事对胎儿肝脏样本中的每一个单独细胞进行了快照式分析。他们的研究主要集中在肝脏，因为它是发育中的胎儿血细胞生成的主要场所之一。这项细胞普查结果与其他研究人员的发现相吻合。

Ana Cvejic

So what we were seeing is what other people also reported before, and that is that we are seeing increase in the number of stem cells, and we were seeing increase in the cells that will make red blood cells and platelets, and there is a decrease or impairment in immune cells, like B cells. And they were using certain set of technologies to observe this, we are now using a different technology. So the first question is, ‘can we actually see something that was described by others using other technologies?’ So if we can see what other people saw, that's kind of reassuring, because it means that our analysis is kind of good enough to capture these changes, and it's a good starting point to then dig deeper into the mechanisms.

我们观察到的现象与之前其他人报告的相似，即造血干细胞数量增加，并且生成红细胞和血小板的细胞数量也增加，而免疫细胞（如B细胞）则减少或功能受损。之前的研究使用了一套特定的技术来观察这些现象，而我们现在使用了不同的技术。因此，第一个问题是：“我们是否能通过这种新技术观察到其他人描述过的现象？”如果我们能看到其他人发现的相同结果，这就意味着我们的分析足够准确，并为进一步深入探究机制提供了一个良好的起点。

Benjamin Thompson

Levels of haematopoietic stem cells are known to increase in the liver of those with Down’s syndrome, but while these stem cells had the potential to become a number of different blood cell types, they were much more likely to follow the path that led to them becoming either red blood cells — also known as erythrocytes — or platelet-forming cells. To understand why, Ana and the team looked at the genomes of these cells to see what effect having an extra copy of chromosome 21 could be having. They showed that it was leading to changes in the way DNA is packaged. Now, DNA isn’t just floating around inside a cell's nucleus as a simple double helix. Essentially, it’s found wound around proteins — like string wound around a set of beads — which compacts and packages it into a structure called chromatin. This packing plays a key role in gene expression — different sections of chromatin on different chromosomes are unwound at different times, allowing specific genes on the DNA to be turned on and off when required. And it turns out the presence of the extra chromosome was changing which DNA was available.

研究表明，唐氏综合征患者的肝脏中造血干细胞水平会升高。虽然这些干细胞有潜力分化成多种不同类型的血细胞，但它们更倾向于发展为红细胞或血小板生成细胞。为了解其中的原因，安娜和她的团队分析了这些细胞的基因组，研究额外的一条21号染色体可能产生的影响。结果显示，这条额外染色体导致了DNA结构的改变。通常情况下，DNA在细胞核内并不是简单的双螺旋漂浮状态，而是缠绕在蛋白质周围——类似于串珠上缠绕的线，从而被压缩成一种称为染色质的结构。这种结构在基因表达中发挥关键作用：不同染色体上的染色质片段在不同时间展开，使得DNA上的特定基因能够在需要时开启或关闭。而事实证明，额外的染色体改变了可用的DNA区域。

Ana Cvejic

So basically, for cell to be a stem cell, it has to have certain properties, and one of these properties is to have the ability to make many different cell types. But it can achieve that by having many different regions open, kind of having options open, like which direction it’s going to go, whereas what we're seeing is a really kind of big restructuring of the chromatin accessibility in the stem cells that they're narrowing down their options so they're actually kind of preferentially opening regions which are going to regulate the gene expression of the erythroid lineage genes, and that is then causing higher expression later on of these erythroid genes, and pushes these cells towards erythroid lineage.

细胞要成为干细胞，必须具备一些特性，其中之一就是能够分化为多种不同的细胞类型。干细胞通过开放多个不同的DNA区域来保证未来分化方向的多样性。而我们观察到的情况是，患者干细胞的染色质发生了很大的重组，使得它们的“选择”范围收窄，优先开放了调控红系基因表达的区域，这随后导致这些红系基因表达水平的增加，将这些细胞推向红系分化方向。

Benjamin Thompson

These ‘regions’ are where things called ‘transcription factors’ can bind. You can think of transcription factors like on/off switches for genes. Changes to the chromatin opened up areas for them to attach, turning on genes related to the proliferation and differentiation of stem cells, which could help explain why high counts of erythrocytes — of red blood cells — are seen in newborns with Down’s syndrome. But what of the increased risk of leukaemia? Well, by making use of previously collected data the team identified that changing the chromatin structure altered the chances of where mutations to the DNA could occur.

这些“区域”是转录因子能够结合的地方。染色质的变化开放了这些区域，允许转录因子结合，从而激活与干细胞增殖和分化相关的基因，这有助于解释为什么唐氏综合征新生儿常常出现红细胞数量增高的现象。那么，他们患白血病风险增加的原因呢？通过先前收集的数据，研究团队发现，染色质结构的变化改变了DNA突变发生的位置，从而影响了突变的发生几率。

Ana Cvejic

We see that these mutations are preferentially happening in these areas in which these transcription factors are going to bind. So you can imagine, if that is mutated, that can cause like transcription factor not to bind or to bind differently, and then can cause changes in gene expression. So at the stage when we are looking, none of these are causative of any phenotypes that we are seeing. But in the future, if some detrimental mutation happens in a right place, then it will cause pre leukaemia and leukaemia.

Benjamin Thompson

The team didn’t see this process happening, but their snapshot of the state of fetal cells gave a sense of what could happen further down the road if damaging mutations occurred, ultimately leading to genes being activated incorrectly. But what could be driving these mutations? It turns out that altering the chromatin structure is doing something else as well.

研究团队并没有看到这个过程的发生，但他们对胎儿细胞状态的快照提供了一个可能的预测：如果发生有害突变，未来可能会发生基因错误激活的情况。那么，是什么推动了这些突变的发生呢？事实证明，染色质结构的改变还引发了其他变化。

Ana Cvejic

So one of the things that also became very clear that is happening in stem cells in the fetal liver was that these cells kind of had changes in a gene expression, which suggested that there is an oxidative stress happening in these cells, and this comes from dysfunction of mitochondria. So these are the what they call the powerhouses inside of the cell, which provide the energy for cell to function.

研究团队还清楚地发现，胎儿肝脏中的干细胞发生了基因表达的变化，这表明这些细胞中存在氧化应激，而这种应激源自线粒体功能障碍。线粒体被称为细胞内的“动力工厂”，它们为细胞提供所需的能量以维持其正常功能。

Benjamin Thompson

Oxidative stress is an imbalanced state where a cell has too many molecules called Reactive Oxygen Species. These have a dual role — they can act as a signalling molecule, but they can also act as molecular wrecking balls, smashing into structures like DNA and causing damage. These Reactive Oxygen Species are thought to play a key role in introducing mutations into the genome of these cells with an extra copy of chromosome 21. And these different pieces, the oxygen species, Ana’s findings about the opening up of certain areas of the genome, and that some areas are more prone to mutation could all come together to help explain why leukaemia risk is so elevated in children with Down’s syndrome.

氧化应激是一种不平衡的状态，细胞中含有过多的活性氧（Reactive Oxygen Species, ROS）。这些分子具有双重作用——它们可以充当信号分子，但也可以损伤细胞内的DNA等结构。研究认为，这些ROS在引入突变中发挥了关键作用。安娜的研究结果表明，ROS、基因组开放区域的变化以及突变的易感性——可以共同解释为什么唐氏综合征儿童患白血病风险如此升高。

Sébastien Malinge

The big strength of this paper is like providing the data on top of explaining many of the phenotypes for many research to come and try to dissect even further.

这篇论文的最大亮点在于提供了数据，并解释了许多表型，为未来的研究提供了基础，研究者们可以在此基础上进一步剖析和探讨。

Benjamin Thompson

This is Sébastien Malinge, a molecular biologist at the Kids Research Institute Australia who studies how leukaemia develops in children. He’s written a News and Views article about the new research. He was impressed by the work and the insights it provides into how blood disorders could begin to come about within fetal livers.

这是塞巴斯蒂安·马林杰（Sébastien Malinge），澳大利亚儿童研究所的分子生物学家，专注于研究儿童白血病的发生机制。他撰写了一篇关于这项新研究的文章，他对这项工作以及血液疾病如何在胎儿肝脏中发生印象深刻。

Sébastien Malinge

It was known that those disorders appeared extremely early, and it was known that it was due to the Trisomy 21 but what was not known is how it works, right? And I think the strength of this work, the strong power of this work, is to give clues about how those things happen. It's been done very deeply, right? They use single cell sequencing to interrogate every single cell to know where those traits are coming from.

人们早就知道这些血液疾病会在非常早期出现，而且知道它们与21号染色体三体性有关，但之前并不清楚其具体机制。对此，我认为这项工作的亮点在于提供了关于这些问题是如何发生的线索。它的深度非常高，对吧？研究人员使用了单细胞测序技术，逐个细胞地分析，弄清楚这些特征是从哪里来的。

Benjamin Thompson

Sébastian says this research provides a strong foundation for future work to further unpick what causes the events to happen, but there’s still much to learn — for instance, he’d like to get a sense of what’s going on with the genome at an even earlier stage.

塞巴斯蒂安表示，这项研究为未来的工作奠定了坚实的基础，以进一步剖析导致这些事件发生的原因，但仍有许多值得探索的内容。例如，他希望能了解在更早阶段基因组发生了什么变化。

Sébastien Malinge

Personally, I would like to know what's happened before. So we see this snapshot of the open chromatin, but how does that happen? Really? We don't know. If it's like a big burst happening at one specific time, or it's a slow process during the several weeks. We don't know. I think it's very interesting question that it's going to be very hard to answer.

我个人想知道的是在这之前发生了什么。我们看到了开放染色质的快照，但它是如何发生的呢？我们其实并不清楚。这是一次性的大规模爆发，还是在几周的时间里逐渐发生的过程？我们并不知道。我认为这是一个非常有趣的问题，虽然很难回答。

Benjamin Thompson

There are lots of other things to understand too. In this work Ana identified a sub-population of stem cells in the liver that seems to cycle a lot faster and have an even more pronounced bias towards ultimately becoming red blood cells. And then there is the fact that what was seen in liver stem cells was not seen in bone marrow cells — another place that blood cells are made. And other tissues can have different gene expression patterns. So what is it about the presence of the extra copy of chromosome 21 that’s driving all this? Ana’s got some ideas.

还有许多其他需要理解的方面。在这项研究中，安娜发现了肝脏中的一个亚群干细胞，这些细胞似乎分裂得更快，并且对最终成为红细胞的偏向性更加明显。还有一个事实是，在肝脏干细胞中看到的现象并没有在骨髓细胞中出现——骨髓是另一种血细胞生成的地方，提示其他组织可能会有不同的基因表达模式。那么，是什么导致了额外的21号染色体的存在，推动了这一切的发生呢？安娜有一些想法。

Ana Cvejic

Clearly, because there is additional chromosome 21 there could be upregulation of the genes which are encoded by chromosome 21 and this is automatically going to change kind of regulatory networks. But you can also think that having additional chromosome for a cell is a burden, because, you know, a lot of things will change in a metabolism of a cell in terms of how much proteins there are and so on. And then you can also think physically, like how all of these chromosomes are packed in the nucleus. So you can think that having additional one can kind of cause some pressure, like on a cell, space-wise.

显然，由于存在额外的21号染色体，这可能导致由21号染色体编码的基因上调，从而自动改变调控网络。但我们也可以考虑到，对于细胞来说，额外的染色体是一种负担，因为这会改变细胞的代谢，例如蛋白质的数量等等。还有，我们可以从物理角度考虑，这些染色体是如何在细胞核中组装的。可以想象，额外的染色体可能会对细胞产生一定的压力，尤其是在空间上。

Benjamin Thompson

Finding out which, or which combination, of these is the driver is going to be difficult. But it’s important to remember that people are at the centre of this. Children with Down Syndrome’s are at a vastly higher risk of leukaemia and both Ana and Sébastian hope this research will be a step in helping to understand why this is. Sebastian says that while leukaemia treatments are available, ultimately not needing them would be a huge benefit to these children.

弄清楚究竟是哪个因素，或哪种因素的组合在驱动这一过程将会很困难。但重要的是要记住，人类是这一研究的核心。唐氏综合症的儿童患白血病的风险极高，安娜和塞巴斯蒂安都希望这项研究能为我们理解这一现象提供一个重要的步骤。塞巴斯蒂安表示，虽然白血病有治疗方法，但最终不需要这些治疗对这些孩子来说将是一个巨大的益处。

Sébastien Malinge

If we can decrease the higher risk of these children to have leukaemia, that would actually be a long-term goal, right. And that's only very important step this paper to start providing some key features to find those indicators. So there’s treatment exists as we save life more than 50 years ago. But like the price is a toxicity and the long-term secondary effect, right of all those toxic treatment so whatever we can find to actually avoid to use life-threatening treatments is a key in the future of research for leukaemia, specifically.

如果我们能够降低这些孩子患白血病的更高风险，那将是一个长期的目标。这篇论文提供了一个非常重要的步骤，为找到这些指标提供线索。因此，虽然目前的治疗方法已经能够拯救生命，但代价是治疗的毒性和长期的副作用。无论我们能找到什么方法避免使用损害生存质量的治疗，都是未来白血病研究的关键。

Benjamin Thompson

That was Sébastian Melinger. You also heard from Ana Cvejic. To read Sébastian’s News and Views article and Ana’s paper, look out for links in the show notes.

这是塞巴斯蒂安·梅林热的发言。你也听到了安娜·克维吉奇的介绍。要阅读塞巴斯蒂安的文章和安娜的研究论文，请查看节目说明中的链接。