Proteins provide important clues to unravelling recurring leukaemia

Leukaemia – one word for different types of blood cancer. Although we are now able to cure some forms of leukaemia, the prognosis for other forms is still very poor (only 25% of all leukaemia patients survive the first five years after the diagnosis). This is probably because cancer stem cells are able to start growing again despite appearing to have been banished by chemotherapy. Researchers from the UK, Germany, Belgium and the Netherlands studied this mechanism and the role that subclones of the cancer stem cells play in this process.

The team is led by Jan Jacob Schuringa, Professor of Experimental Haematology at the University Medical Center Groningen. During their search, the researchers found an important part of the puzzle. This month, they published an article on the subject in the scientific journal Cancer Cell.

How is our blood formed?

Our blood is formed by specialized stem cells in our bone marrow. When one of these stem cells divides, it produces a copy of the mother cell (i.e. a new stem cell), and one daughter cell which continues to divide and develop into three different types of blood cells: red blood cells, white blood cells and blood platelets. The stem cells divide very slowly, while the daughter cells are highly active, producing a continuous supply of new cells in our bone marrow. Patients with leukaemia are usually treated with chemotherapy. Although this may initially appear to be effective, unfortunately the illness recurs in almost 75% of the cases. This is because chemotherapy was developed specifically to attack rapidly dividing cells. This works effectively on daughter cells, but not on cancer stem cells, which divide much more slowly. This is why the cancer often returns in time. The researchers went in search of a different point of intervention, which would ensure that the chemotherapy could attack all of the right cells (the rapidly dividing daughter cells and the slowly dividing cancer stem cells).

The fault in our DNA

Leukaemia is caused by abnormalities in our DNA (i.e. faults in the genes). Around 250 different DNA abnormalities that cause leukaemia have been found. Most patients do not develop leukaemia because of one such abnormality, but because they have a combination of 3 to 7 abnormalities. In fact, some patients even have several different combinations of DNA abnormalities. The first abnormality that develops will appear in all leukaemia cells, but the subclones of the cancer stem cell that subsequently develop will each have their own combination of DNA abnormalities. So every patient is different, but more importantly, the ideal treatment for each patient is also different. To find treatment methods, researchers must first find a way to unravel these subclones. This is precisely what these researchers have done. They identified 50 proteins in the cell membrane (the outer casing) of leukaemia cells. These proteins are unique to cancer cells and are not present in normal, healthy stem cells. The combinations of these proteins are always different and unique to the subclone of the cancer stem cell. And this the key: the proteins do not only make it possible to identify specific cancer cells, but they can also be used to isolate them. It is important because by separating the subclones from the other types of leukaemia cells, the researchers discovered that cells are actually very different from each other, including in their sensitivity to certain drugs, for example. Using this knowledge, we will now be able to develop better medicines to target specific subclones. This will then allow us to modify medicines so that they only attack cells containing precisely these proteins – a new point of intervention.

Still a long way to go…

The proteins thus identified are extremely useful in terms of recognizing leukaemia cells. The UMCG is already using this knowledge by looking for the seven most common proteins when diagnosing leukaemia. But the researchers are also trying to discover whether they can use the proteins to predict whether, and if so which, subclones will start to grow again, enabling them to intervene at the earliest stage possible. Their ultimate aim is to make a cocktail of drugs for the specific DNA abnormality combination of every individual patient, thereby targeting the proteins that lead to the right cancer cells. Now that’s what we call ‘personalized medicine’.