The complex fight against leukaemia

The mouse hospital

In a small room, hidden away in the depths of the UMCG building, cell biologist Jan Jacob Schuringa has set up his mouse hospital. His mice have the same kind of cancer as the UMCG’s ‘real’ patients. What works on them, might work for human beings as well.
By Christien Boomsma / Photos by Reyer Boxem / Translation by Sarah van Steenderen

Getting to Jan Jacob Schuringa’s hospital is not an easy feat. First, you have to go through a door that can only be opened with a key card. Next, you have to exchange your shoes for a pair of plastic clogs and don a pair of special pants and a special sweater. Then you have to make your way to the next room, where you change clothes once again: new plastic clogs; a disposable overcoat; a face mask; and a hair net.

Only then are you allowed to visit Schuringa’s patients.

And there’s good reason for this. The hospital is for mice, and its patients are xenografted mice: their immune systems are defective to allow Schuringa to grow human cells in the mice. But this also makes them extremely susceptible to outside viruses and bacteria. On top of that, they also have leukaemia, or will get it soon.

Grow old

‘Not this one, I hope’, Schuringa says, pointing to the twitchy little nose behind the glass of a habitat on the second row from the top. In this particular mouse, the KDM2B gene has been switched off in the stem cells she has been injected with. This means she’ll probably grow old normally and will not get leukaemia.

At this moment, approximately fifteen of the 54 ‘beds’ in Schuringa’s mouse hospital are taken, by approximately thirty animals in total; they share their accommodation. They’ve each been injected with cells from human leukaemia patients. This allows Schuringa to not only see how the disease develops, but he can also test treatment methods. Because if you can cure a mouse, maybe you can also cure a human being.

Leukaemia is caused by mutation in the hematopoietic stem cells in DNA. These are stem cells that produce the mature blood cells that form healthy blood. ‘These blood stem cells are hidden deep within the bone marrow, and don’t divide very often’, Schuringa says. ‘Approximately once a month. But when a blood stem cell does divide, it not only copies itself, but also creates a progenitor cell, which then continues dividing. This eventually becomes an immune cell, a red blood cell, or platelets.’

Five mutations

In people with leukaemia, however, something goes wrong during this process. The progenitor cells do not have the right programming. They pile up in the bone marrow, while the blood starts suffering from a lack of white blood cells, causing the immune system to stop functioning properly. ‘What we also know’, says Schuringa, ‘is that one mutation isn’t enough.’ People need five to ten mutations in order to develop leukaemia.’

The good news is that we know which gene mutations are related to leukaemia, and that there are approximately 250. The bad news is that they occur in countless different combinations. ‘This makes each patient unique.’

Schuringa is trying to see the forest through the trees. ‘We know which genes are involved’, he says. An impressive diagram on a screen on his wall shows all the different known mutations in the combination they have occurred in in two hundred patients. ‘Our next step is to figure out what each mutation does exactly. Which processes are affected when you turn a specific gene on or off?’


In the case of Chronic Myeloid Leukaemia (CML), for example, this method has led to proper treatment. The drug Glenvec is working wonders, because it intervenes with a mutated protein on the cancer cell, thereby killing it. But the medical world still lacks knowledge on many of the other mutations.

It’s also important to know whether the mutations occur in any specific order. ‘Acute Myeloid Leukaemia (AML) creates mutations in the epigenetic machinery, although that doesn’t lead to symptoms. It’s not until several mutations accumulate that leukaemia arises’, says Schuringa. Defeating the first mutation in a mouse does not mean that the leukaemia is stopped. The second mutation has to be blocked as well. ‘It looks like we’re booking better results with that, but we’re still in the middle of the research.’

The mice in the mice hospital are needed to translate these kinds of fundamental insights into treatment methods. Scientists can do endless research in test tubes, but proper conclusions can only be drawn after in vivo research. And that means live mice are needed.

From the freezer

As soon as Schuringa can make assumptions based on in vitro experiments, he takes his mutated stem cells from the freezer and puts them in a mouse to see if he can block the development of leukaemia. This might not immediately lead to treatment for human beings, as you can’t just go around messing with cancer patients’ DNA, it does offer important insights that can help the research.

But Schuringa also made other discoveries in his mouse hospital, which come much closer to the daily reality of patients. He is also trying to identify the rare leukaemic stem cells and their rapidly-dividing daughter cells that ultimately create tumours. ‘We’re doing this by looking at which proteins exist on the outside of the cells’, Schuringa says. ‘We can then use these to discern the leukaemia cells from the healthy cells, and potentially target them by attacking them with certain drugs.’

He has found sixty of these proteins so far. His research is so useful, that the UCMG’s diagnostics lab has been testing for seven of these proteins in patients. They can be used to track down malignant cells and might at some point even be able to predict early on whether the disease will recur. ‘But we also want to specifically aim new drugs at those cells.’


There is a great need for new treatment methods for leukaemia. Stem cell transplants and chemotherapy are still the most-used methods, but their success is limited. ‘At the beginning they always seem to work fine’, says Schuringa. ‘But chemo mainly attacks the rapidly-dividing progenitor cells, not the slowly-dividing leukaemic stem cells. Even if only a few of them remain, they will eventually lead to a relapse.’

Another problem is something Schuringa has called the ‘clonal heterogeneity’. ‘For a long time, people thought that cancer developed in a linear way, a sort of survival of the fittest where one clone wins and starts growing in the patient’, he explains.

But the option of studying cancer at the single-cell level has clearly shown that this thought was incorrect. ‘A single tumour can contain various clones, each with its own mutations. So treating the cancer by eliminating one clone could mean that you’re not eliminating the others. And then the cancer will come back.’


The different proteins in the different clones, however, allow scientists to differentiate between them. This means they can be fought separately.

‘You might fight clone one using drug one’, he says. ‘And clone two with drug two.’ He suspects that because of this research, certain substances that haven’t led to new medication discoveries will be re-examined. ‘They might not work against all tumour cells, but just against one type of cell.’

In other words: the field is quickly developing. ‘We may not have made much progress over the past few years, but at least now we know why the disease is so hard to treat. And that’s why I think that in the very near future, we’ll be able to make great leaps in fighting it.’



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