Understanding what causes childhood leukaemia
Leukaemia is the most common type of cancer in children. However, thanks to optimised treatment regimes, there is now a 90 % survival rate – up from just 10 % in the 1960s. Unfortunately, this good news comes with a price. “The aggressive chemotherapy used to treat leukaemia can cause a number of side-effects, including infertility, IQ problems, and an increased risk of developing secondary tumours later in life,” says Pieter Van Vlierberghe, a researcher at Ghent University. Clearly, there is a need for more effective and less toxic anti-leukaemic drugs. However, a prerequisite for developing drugs with a greater degree of specificity first requires that researchers have a better understanding of the molecular events that lead to leukaemia – which is exactly what the EU-funded EpiTALL project set out to do. “First, we wanted to understand the molecular mechanisms that drive aberrant DNA methylation in childhood leukaemia,” explains Van Vlierberghe, who served as the EpiTALL project coordinator. “We also evaluated if therapeutic targeting of the DNA methylation machinery could serve as a novel strategy for treating this aggressive disease.”
A breakthrough understanding
DNA methylation is an epigenetic feature that, at least in part, can impact gene expression at a genome-wide level. However, because DNA methylation is altered in many cancer types, it holds significant prognostic and diagnostic value. Knowing this, the EpiTALL project, which was supported by the European Research Council, compared DNA methylation profiles from a large cohort of human leukaemia patients with their healthy counterparts. “What we found is that DNA methylation in childhood leukaemia mainly occurs in target genes that hardly show any expression in normal or leukaemic tumour cells,” notes Van Vlierberghe. “In contrast, we revealed that aberrant DNA methylation actually shows a strong correlation with the proliferative history of leukaemic cells, rather than with leukaemia-specific gene expression patterns.” This breakthrough understanding of the different developmental trajectories that leukaemia takes could play a fundamental role in designing anti-leukaemic therapies that eradicate leukaemic cells from the initiating cells onwards. “For example, our research showed that decitabine, an approved DNA methylation inhibitor, has an anti-leukaemic effect in preclinical models,” adds Van Vlierberghe. “This gives us hope that this agent could serve as a new therapeutic strategy for treating childhood leukaemia.”
Next steps include more research
According to Van Vlierberghe, the project succeeded in demonstrating how DNA methylation reflects the epigenetic history of leukaemia cells. “This suggests that methylation-based subtypes of human leukaemia might have followed a different trajectory towards malignant transformation, possibly mediated by differences in the self-renewing capacity of their putative cell-of-origin,” he concludes. To confirm, researchers are working to functionally validate the molecular mechanisms that drive the aberrant DNA methylation signatures identified by the EpiTALL project. Van Vlierberghe is currently setting up a trial that will evaluate the safety and efficacy of DNA methylation inhibitors within the context of childhood leukaemia.
Keywords
EpiTALL, childhood leukaemia, leukaemia, cancer, chemotherapy, anti-leukaemic drugs, DNA methylation, gene expression
