What’s going on in leukaemic cells?
UEF Bulletin 2017
Cell regulatory networks may offer new targets for the treatment of acute childhood leukaemia.
Over the last few decades, survival rates from acute childhood leukaemia have increased considerably, thanks to improved treatments. Today, as many as 85 per cent of patients survive. However, some types of leukaemia respond poorly to treatment, and one in five patients relapse.
According to Academy Researcher Merja Heinäniemi, more tailored treatments are needed. At the moment, all children with acute leukaemia undergo intensive cytostatic therapy. The aim is to rid the body of leukaemic cells, but the treatment is toxic to healthy cells as well and can cause serious side effects, even secondary cancers later in life. “Thus, it is important to develop less aggressive treatments for lower-risk leukaemia subtypes.”
On the other hand, patient groups with poor prognosis, such as infants with leukaemia, need new and more effective therapies suited to their specific types of disease.
This calls for more detailed knowledge of the disease mechanisms. Like cancers in general, acute childhood leukaemia is caused by genetic alterations, as well as epigenetic changes affecting gene activity and expression. The first genetic changes predisposing to leukaemia often occur before birth, but cancer only develops in the presence of additional harmful alterations. Many genetic mutations linked to leukaemia are already known, but there is a lot of diversity between patients, and even in a single patient, some cancer cells may carry different mutations than others.
Researchers have become increasingly aware that it's not only the mutations in the coding DNA that matter in leukaemia. “Changes in DNA regulatory elements and transcription play a role too. Cancer cells are a dysfunctional system, so it makes sense to take a look at their regulatory networks," Heinäniemi says.
Transcription is the first step in gene expression. Regulatory elements are non-coding regions of the DNA that regulate the transcription of the coding regions.
“Mutations in regulatory elements or changes in their activity might explain some previously unexplained leukaemia cases. It’s also interesting to find out if there are differences in the activity of regulatory elements between the presently known subtypes of leukaemia.”
To analyse the regulatory networks in leukaemic cells, Heinäniemi, who leads a research group at the UEF Institute of Biomedicine, has taken up deep sequencing methods like global run-on sequencing, or GRO-seq, that yields a detailed and dynamic overview of transcription in the cells. Such an approach has never been applied in leukaemia research before. With expertise in systems genomics, bioinformatics and machine learning methods, her team can pinpoint the relevant changes from the vast amounts of resulting information.
Using patient samples and cell lines, together with Docent Olli Lohi's team at the University of Tampere, they recently found that up to 90 per cent of recurrent DNA lesions in the most common childhood leukaemia can be explained by disturbances in blood cell gene transcription. They showed for the first time that these damages occur in regions where the DNA is being transcribed particularly actively, and where the transcription process slows down locally. In this situation, damage-causing enzymes get a chance to attack the DNA that is “unzipped” from its two-stranded form for transcription and is thus more vulnerable to damage.
As more research data on such mechanisms accumulates, future therapies could possibly dampen their activity, reducing genetic instability and thus leading to better treatment results and a smaller risk of relapse.
In the same study, the researchers identified a new subtype of high-risk leukaemia, characterised by an altered expression of enzymes that cause DNA damage.
The genetic changes in acute childhood leukaemia often involve fusions or deletions of transcription factors that regulate blood cell development and differentiation. The most common is the ETV6-RUNX1 fusion gene, which is carried by one in four patients. It was identified two decades ago, but its exact genomic targets haven't been known until recently. A comprehensive genome-wide mapping carried out by Heinäniemi's and Lohi's groups showed that the fusion gene altered the expression of approximately two hundred genes and the activity of previously unknown regulatory elements, the so-called enhancers.
One impact of the repressive effect of the fusion gene on enhancers was the down-regulation of genes participating in cellular signalling and adhesion, which may indicate an altered interaction of leukaemic cells with their environment.
“In our future research, we intend to focus even more on cell-cell interactions. A variety of cell types coexist and communicate in the bone marrow. Their interaction might offer a clue as to why some leukaemic cells may persist in the bone marrow after treatment,” says Heinäniemi, who was recently awarded a Jubilee Grant for this line of research by the Väre Foundation.
She became intrigued by the complexity of leukaemia as early as her high school years, when she volunteered on a children’s cancer ward. Now her research choices and experience have taken her to a point where it may actually be possible to pave the way for new treatments. The importance of her approach shows in the significant funding she has received. She also has a tenure in bioinformatics at UEF.
Alongside research, an important recent project has been the interdisciplinary Nordic leukaemia workshops supported by the Finnish Cultural Foundation. The funding has enabled Heinäniemi and Lohi to bring clinicians together with researchers representing expertise in genomics, disease models, bioinformatics and engineering. By joining forces and genome-wide materials, the collaboration has aimed at introducing new methodology and approaches for profiling leukaemia subtypes on a molecular level to researchers with different backgrounds, and at recognising new drug targets for different subgroups.
“It’s vital to share expertise and to narrow the gap between researchers and clinicians, so that research findings can actually be put to use in the treatment of patients,” Heinäniemi says.
She is confident that whole-genome-sequencing, for example, will become a standard diagnostic tool in acute childhood leukaemia in the future, allowing us to choose the most suitable treatment. At the moment, only the most common mutations are tested.
Her research group takes part in identifying new drug candidates as well. “Both new and repurposed drugs could offer treatment alternatives. We are also developing a tool to support drug discovery and treatment planning.”
Acute childhood leukaemia
- Leukaemia is the most common childhood cancer.
- Leukaemia is a cancer of the blood cells and it begins in the bone marrow where blood cells are produced.
- Acute lymphocytic leukaemia (ALL) is the most common form of leukaemia in children, and most of the remaining cases are acute myeloid leukaemia (AML).
- Patients are divided into standard, intermediate and high risk groups. For all, cytostatics are the main treatment.