Combating Acute Myeloid Leukemia Relapse Through Stem Cell Biology
Researchers have identified two distinct stem cell–like populations from which relapse can arise in AML patients, which may help clinicians identify who will and won't respond to standard chemotherapy.
Relapse in acute myeloid leukemia (AML), in part, may be due to rare therapy-resistant leukemia stem cells that are already present at diagnosis and before chemotherapy begins, according to Canadian researchers. Reporting in the journal Nature, they have identified two distinct stem-cell–like populations from which relapse can arise in different AML patients.
The findings provide significant insights into cell types fated to relapse and may help accelerate the quest for novel upfront therapies. “We found the cells that cause AML to come back after successful initial therapy. These cells were present at the time of diagnosis, but were a small fraction of all cells,” said first author of the study, Liran Shlush, MD, PhD, from Princess Margaret Cancer Centre, University Health Network, Toronto, Canada. “For the future we should target these cells specifically. We should monitor for their existence to better predict who is going to relapse and treat them earlier.”
By combining the knowledge ascertained about stem cell biology with genomics it has become possible to identify specific mutations that stem cells carry, according to study investigator John Dick, PhD, a professor in the Department of Molecular Genetics at the University of Toronto. The team analyzed paired patient samples of blood taken at the initial clinic visit and blood taken post-treatment when the disease recurred. They carried out detailed genetic studies and used whole genome sequencing to look at every part of the DNA at diagnosis. They also examined the DNA at relapse to determine what genetic changes may have occurred.
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 and then focus on the specific cell types fated to relapse. The researchers identified two major patterns of relapse: one originated from rare leukemia stem cells with a hematopoietic stem/progenitor cell phenotype; the other suggested that relapse may have developed from larger subclones of immunophenotypically committed leukemia cells that retained strong stemness transcriptional signatures. Stemness is defined as an essential characteristic of a stem cell and different from ordinary cells. Cancer stem cells differentiate into cancer cells, unlike normal stem cells, and the stemness of cancer stem cells can be determined by various signaling pathways.
The study authors hope these findings will lead to a new biomarker that clinicians can use in advance to identify AML patients who will respond to standard chemotherapy. They also hope these findings will help identify a biomarker that could track patients in remission and help guide therapy.
"It's not random,” Dr. Shlush told OncoTherapy Network. “Cellular context is important. Not all cells in the tumor are equal.”
