Grant: Doctoral Research Award: Canada Graduate Scholarships

Myelodysplastic Syndrome (MDS) is a common cancer of the blood and bone marrow. It causes low blood counts, which can lead to serious problems. A major cause of MDS is changes to how active the genes are by a process called methylation, which we can determine by advanced gene sequencing (whole-genome bisulfite sequencing, WGBS). For most MDS patients, the only treatment is a chemotherapy called 5-azacitidine (5-aza). In 40% of patients it doesn't work but can cause many side effects (infection, death), reduce quality of life, and is expensive ($60,000 CAD/year). We cannot predict who will not respond, other than by trying several months of treatment. Preliminary data obtained by analysing the methylation patterns in 8 MDS patients suggests chemotherapy resistance is due to changes that alter the structure of bundles of cellular DNA (chromatin). Additional data suggests that this results in cells appearing more mature in chemotherapy resistant (LMPP) vs sensitive patients (MPP). We hypothesise that changes to methylation in genes controlling chromatin structure results in MDS cancer cells being either more mature (LMPP) or less mature (MPP), and that the LMPP patients are chemotherapy resistant. Our goal is to develop a test that will allow us to predict which patients will be resistant to the 5-aza chemotherapy. Our aims will be to first confirm the preliminary data by testing methylation in purified mature (LMPP-like) and immature (MPP-like) MDS patient cells. We will then directly look at the chromatin structure with Hi-C chromatin capture. Finally, we will recruit 47 MDS patients being treated with 5-aza to see if we can retrospectively predict chemotherapy sensitivity by measuring methylation. Developing a test to predict chemotherapy sensitivity in MDS patients will save many patients bad side effects and reduce healthcare costs. Understanding why patients do not respond to 5-aza will also pave the way for new treatments in MDS and related blood cancers.