What causes leukaemia and how can we use this information to better treat it?
2nd Feb 2020
Since it is blood cancer awareness month, I thought I would do a post about what research we are currently doing to figure out why blood cancer starts in the first place. I am a research scientist, and I have a number of different projects on the go, which is fairly normal for someone at my career stage. One of these projects looks at how certain leukaemias may be more sensitive to some chemotherapy drugs due to specific problems with their DNA (called DNA mutations), but many of my projects concern how leukaemia develops in the first place. So that we can effectively treat leukaemias, or even possibly prevent them in the future, we have to understand why they happen in the first place. There has been a lot of Leukaemia and Lymphoma Research funded work in this area, especially in childhood acute lymphoblastic leukaemia (ALL), for example the work done by Professor Mel Greaves and his team.
My PhD project looked at how this happens in a particular type of acute myeloid leukaemia (AML), which is caused by a ‘fusion gene’. Humans have around 25,000 different genes, which produce distinct proteins, controlling a number of different processes in the body, and normally, all of these genes are arranged very precisely on large coiled bits of DNA called chromosomes. In some types of leukaemia, two genes become joined together abnormally – which means rather than producing two separate proteins, they produce two proteins joined together, which stops them working properly. Imagine trying to do everything you had to do in a day, if you had to do it joined together with another person , who wanted to do entirely different things. In this case, the two proteins joined together are called AML1 and ETO. AML1 when working well and on its own is very important for guiding the production of healthy blood cells, but when joined together with ETO, it doesn’t work properly. However, in this case, if AML1-ETO is in a blood stem cell in the bone marrow, it isn’t quite enough to cause a leukaemia – but we think what it does do is makes that cell more vulnerable to gaining other DNA mutations – some of those can then go on to make that cell into a leukaemia cell.
As humans, we have 23 pairs of chromosomes, numbered 1-22, plus an extra pair, which determine whether we are male or female (XX for females and XY for males). When a patient gets diagnosed with leukaemia, a sample of their cells is taken to the lab for an analysis called ‘karyotyping’ – this means that scientists called cytogeneticists use a microscope to look for changes to the structure of the chromosomes of that cell, which may give clues as to what has caused that leukaemia. For example, in the case of AML1-ETO mentioned above, the AML1 gene on chromosome 21 gets joined to the ETO gene on chromosome 8. However not all leukaemias are caused by fusion genes. As anyone who has read my previous blogs will know, I had leukaemia when I was a child. A couple of years ago, at a routine checkup, I asked my consultant if she had any more information about the DNA mutations that caused my leukaemia. The first part of my karyotype (picture: above right) says that my leukaemia cells had 46 chromosomes, which is normal for human cells which are not gametes (sperm and egg cells), which have half. In lots of leukaemias, there are more or less chromosomes than there should be. The second part, the XX – just shows that I am female (which I already knew!) – but the last part ‘del(6)(q15-q23)' indicates what may have gone wrong in that cell to cause the leukaemia. It means that part of chromosome 6 was lost in those cells – and along with it, hundreds of genes some of which may have been involved in regulating blood cell production, although it is impossible to tell retrospectively whether this or another tiny DNA mutation that couldn't be seen by cytogeneticists was responsible for my leukaemia.
By finding out more about these DNA mutations which cause leukaemia, we can find better ways to treat leukaemia. For example, another fusion gene found in a type of leukaemia called acute promyelocytic leukaemia (APL), called PML-RARA, causes leukaemia by stopping blood cells developing properly. Research on PML-RARA showed that these patients were particularly sensitive to a drug called ATRA, which stops PML-RARA from blocking the blood cells from developing properly. Thanks to this research and understanding of what caused the leukaemia in the first place, around 90% of these patients achieve at least 5-year survival, whereas before this, the survival chance was dismally low.
I hope you have enjoyed reading this blog, and thank you for all of your messages. Please do feel to ask my any questions by commenting here on the blog, or by tweeting me @vickyyyf If there is something which you would like me to write about, let me know! Thank you to Leukaemia and Lymphoma Research scientist and qualified cytogeneticist Dr. Sarah Fordham for the picture of her own chromosomes!