Chemical stem cell signature predicts treatment response for acute myeloid leukemia
A chemical signature has been found in blood-forming stem cells that predict if a patient with acute myeloid leukemia (AML) will respond to chemotherapy. The findings are based on data from nearly 700 AML patients. If validated in clinical trials, the signature would help in identifying which AML patients would benefit from chemotherapy and which patients have a prognosis so grave that they may be candidates for more aggressive treatments such as bone marrow transplantation.
According to the American Cancer Society, AML accounts for nearly one-third of all new leukemia cases each year. In 2013, more than 10,000 patients died of AML.
"AML is a disease in which fewer than 30% of patients are cured," said cosenior author Ulrich Steidl, MD, PhD, of Albert Einstein College of Medicine and Montefiore Medical Center in New York, New York. The study was published in the Journal of Clinical Investigation (2014; doi:10.1172/JCI71264). "Ideally, we would like to increase that cure rate. But in the meantime, it would help if we could identify who won't benefit from standard treatment, so we can spare them the debilitating effects of chemotherapy and get them into clinical trials for experimental therapies that might be more effective."
The study focused on epigenetic marks, which are chemical changes in DNA that turn genes on or off. The researchers focused on one common epigenetic process known as methylation, in which methyl groups attach in various patterns to the genes of human cells. Researchers have known that aberrations in the methylation of hematopoietic—or blood-forming—stem cells (HSCs) can prevent them from differentiating into mature blood cells, leading to AML.
Steidl suspected that comparing how closely the DNA methylation patterns in the cancerous white blood cells of AML patients resembled the patterns found in healthy individuals' HSCs might foretell the patients' response to treatment. To find out, the scientists carried out a novel DNA methylation analysis on 561 genes in healthy HSCs at various stages of differentiation.
The researchers first analyzed HSCs from three healthy individuals to determine normal methylation patterns. They found that in the HSCs of healthy people, most DNA cytosines (one of four main components of DNA) are methylated. They noted that where demethylation (removal of methyl groups) occurs, it is limited mainly to one particular stage of HSC differentiation.
The researchers hypothesized that, by comparing the epigenetic signature of healthy people's HSCs with that of AML patients' cancerous white blood cells, they could predict survival of AML patients. Patients with AML whose HSCs were more like healthy people were hypothesized to be more likely to live longer.
The researchers then tested their scoring method using data on 688 AML patients in three different clinical trials. In each of these groups, patients with low scores had approximately twice the median survival time of patients with high scores. "Our epigenetic stem cell signature was clearly superior to similar tests that have been used," said Steidl.