Stem cells present at diagnosis reveal which AML patients will relapse

Relapse in patients with acute myeloid leukemia (AML) may be caused by rare therapy-resistant leukemia stem cells already present at diagnosis, according to researchers who have published their findings in Nature.

"For the first time, we have married together knowledge of stem cell biology and genetics – areas that historically have often been operating as separate camps – to identify mutations stem cells carry and how they are related to one another in AML," said lead author John Dick, PhD, FRS, senior scientist, Princess Margaret Cancer Centre, University Centre, University Health Network, and Professor in the Department of Molecular Genetics, University of Toronto, Ontario, Canada, who pioneered the cancer stem cell field by identifying leukemia stem cells in 1994.

Dr. Dick—who holds the Canada Research Chair in Stem Cell Biology and is Co-leader of the Acute Leukemia Translational Research Initiative at the Ontario Institute for Cancer Research, and fellow researchers analyzed paired patient samples of blood taken at their initial clinic visit, and blood taken after treatment and disease recurrence in AML patients.

"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 Dr. Dick. "Next, we asked in which cells are genetic changes occurring."

They found a set of mutations seen only at relapse, and were able to sort leukemic and normal stem cells using tools developed by Dr. Dick that allowed them to focus on the specific cell types bound to relapse.

"This is a story that couldn't have happened 5 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," he said.

These results lend support to previous research published in the December 7, 2016 issue of Nature, in which researchers developed a “stemness biomarker,” comprised of a 17-gene signature derived from leukemia stem cells that was predictive, at diagnosis, of which AML patients would respond to standard treatment.

"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,” noted Dr. Dick.

"These new kinds of biomarkers will lead to new kinds of clinical trials with targeted chemotherapy. Right now, everybody gets one-size-fits-all because in AML we've never had any opportunity to identify patients upfront, only after they relapse. Now we have the first step to identify these patients at the outset and during remission," he concluded.