Rare therapy-resistant leukemia stem cells are responsible for causing relapse in acute myeloid leukemia (AML) patients, according to findings of a study conducted by Ontario-based researchers.
Prior to this, physicians never had any opportunity to identify AML patients up front, only after they relapse, said Dr. John Dick, who led the team of leukemia researchers.
“Now we have the first step to identify these patients at the outset and during remission,” he said. “Our new findings add to that knowledge and we hope that we will soon have a new biomarker that will tell whether a patient will respond to standard chemotherapy, and then another to track patients in remission to identify those where treatment failed and the rare leukemia stem cells are coming back.”
The researchers are hopeful that the new biomarkers will lead to new kinds of clinical trials with targeted chemotherapy.
Dick is a senior scientist at Princess Margaret Cancer Centre, University Health Network, and professor in the Department of Molecular Genetics, University of Toronto. He holds the Canada Research Chair in Stem Cell Biology and is Director of the Cancer Stem Cell Program at the Ontario Institute for Cancer Research. This study was primarily undertaken by post-doctoral fellow Dr. Liran Shlush and scientific associate Dr. Amanda Mitchell.
Their findings, which was published in Nature (doi:10.1038/nature22993) – provide significant insights into cell types fated to relapse and can help accelerate the quest for new, upfront therapies.
The research was funded by the Ontario Institute for Cancer Research, the Cancer Stem Cell Consortium via Genome Canada and the Ontario Genomics Institute, the Canadian Institutes of Health Research, the Canadian Cancer Society, the Terry Fox Foundation, a Canada Research Chair and The Princess Margaret Cancer Foundation.
Dick pioneered the cancer stem cell field by identifying leukemia stem cells in 1994. A decade ago, he replicated the entire human leukemia disease process by introducing oncogenes into normal human blood cells, transplanting them into xenografts (special immune-deficient mice that accept human grafts) and watching leukemia develop – a motherlode discovery that has guided leukemia research ever since.
He said this research conducted by the team represents the marriage of stem cell biology and genetics. These two areas have historically operated as separate camps.
The researchers set out to solve the mystery of AML relapse by analyzing paired patient samples of blood taken at the initial clinic visit and blood is taken post-treatment when disease recurred.
“First, we asked what are the similarities and differences between these samples. We carried out detailed genetic studies and used whole genome sequencing to look at every part of the DNA at diagnosis, and every part of the DNA at relapse,” said Dick. “Next, we asked in which cells are genetic changes occurring.”
The two-part approach netted a set of mutations seen only at relapse that enabled the team to sift and sort leukemic and normal stem cells using tools developed in the Dick lab a few years ago to zero in on specific cell types fated to relapse.
“This is a story that couldn’t have happened five years ago, but with the evolution of deep sequencing, we were able to use the technology at just the right time and harness it with what we’ve been working on for decades,” Dick said.