Interrogating the evolving clonal structure of leukemia from diagnosis to relapse

Understanding why aggressive leukemias become resistant to therapy

Acute myeloid leukemia (AML) is a rare but aggressive form of blood cancer that affects just over a thousand Canadians every year. While existing therapies used to treat AML are successful in helping to initially stave off the disease, most patients eventually become resistant to these drugs and relapse, leading to a very low five-year survival rate of only 28 per cent. 

In this context, addressing therapy resistance is key to improving the survival of patients diagnosed with AML. But for this to happen, researchers must first understand why it occurs to begin with. 

“We know that in some cases, additional changes to the DNA letter code, or mutations, are responsible for resistance,” explains Dr. Aly Karsan, a Distinguished Scientist at Canada's Michael Smith Genome Sciences Centre at BC Cancer. “However, about half the time, we cannot find new mutations that would cause resistance, and this is something we really need to address.” 

To start bridging this gap, the Marathon of Hope Cancer Centres Network (MOHCCN) will provide funding to a team of pan-Canadian researchers in Vancouver, Toronto and Montreal led by Dr. Karsan and Dr. David Sanford to collect clinical data and sequence the whole genome and transcriptome of patients’ AML cells. The team will use additional funding from other sources to sequence the patients’ leukemias at the time of relapse.  

With this information, and information from other experiments, such as single cells analysis, the team will be able to compare the epigenome at diagnosis and at the time of relapse to better understand what mutational and non-mutational changes might be responsible for therapy resistance. 

“Understanding the genomic and epigenomic mechanisms that make AML, and cancer in general, resistant to therapy is critical to enable long-term cures for patients,” says Dr. Karsan. 

Contributing to a greater effort 

MOHCCN funding for this project comes from as part of the Network’s Pan-Canadian Project program. This new program is uniting researchers and clinicians from multiple provinces to work on projects that accelerate precision medicine for cancer in Canada. 

As part of the funding envelope, Dr. Karsan and his team have committed to contributing all the clinical and genomic data collected as part of the study to the MOHCCN Gold Cohort, the largest and most complete cancer case resource in Canada. This resource will then be used by researchers across the country to see why patients respond to specific drugs in order to eventually match each cancer patient to the right treatment at the right time for their particular cancer.