Researchers Discover Preleukemic Stem Cell at Root of AML Relapse
Researchers have discovered a preleukemic stem cell that may be the first step in initiating disease and also the culprit that evades therapy and triggers relapse in patients with acute myeloid leukemia (AML). The research, published online in Nature, is a significant step forward in understanding the steps that a normal cell has to go through as it turns into AML, said John E. Dick, PhD, of University Healthy Network and University of Toronto. The findings have the potential to advance personalized cancer medicine by identifying individuals who might benefit from targeting the preleukemic stem cell.
"Our discovery lays the groundwork to detect and target the preleukemic stem cell and thereby potentially stop the disease at a very early stage when it may be more amenable to treatment," said Dr. Dick. "Now we have a potential tool for earlier diagnosis that may allow early intervention before the development of full AML. We can also monitor remission and initiate therapy to target the preleukemic stem cell to prevent relapse," he said.
Study Findings
The findings show that in about 25% of patients with AML, a mutation in the gene DNMT3a causes preleukemic stem cells to develop that function like normal blood stem cells but grow abnormally. These cells survive chemotherapy and can be found in the bone marrow at remission, forming a reservoir of cells that may eventually acquire additional mutations, leading to relapse.
The discovery of preleukemic stem cells came out of a large Leukemia Disease Team that Dr. Dick assembled and included oncologists who collected samples for the Princess Margaret Cancer Centre Biobank and genome scientists at the Ontario Institute for Cancer Research who developed sophisticated targeted sequencing methodology. With this team, it was possible to carry out genomic analysis of more than 100 leukemia genes on many patient samples. The findings also capitalized on data from more than 6 years of experiments in Dr. Dick's lab involving growing human AML in special mice that do not reject human cells.
Potential New Target for Drug Development
"By peering into the black box of how cancer develops during the months and years prior to when it is first diagnosed, we have demonstrated a unique finding. People tend to think relapse after remission means chemotherapy didn't kill all the cancer cells. Our study suggests that in some cases the chemotherapy does, in fact, eradicate AML; what it does not touch are the preleukemic stem cells that can trigger another round of AML development and ultimately disease relapse," said Dr. Dick, who anticipates the findings will spawn accelerated drug development to specifically target DNMT3a.
These findings may also provide impetus for researchers to look for precancerous cells in AML patients with other mutations and in nonhematologic cancers cancers.
Dr. Dick is the corresponding author for the Nature article.
The research was supported by the Cancer Stem Cell Consortium, the Canadian Institutes of Health Research, Canadian Cancer Society, Terry Fox Foundation, the Government of Canada, Ontario Institute for Cancer Research, and The Princess Margaret Cancer Foundation.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
