Acute lymphoblastic leukemia is a common childhood cancer that is known to be caused by a number of genetic alterations. Determining what those genetic alterations are at the time of diagnosis may be the key to deciding which treatments to use and determining the probability of patient relapse, says St. Jude Children's Research Hospital's Charles Mullighan. While he has conducted several studies on leukemia-associated mutations over the past several years, Mullighan has also begun to look into the nature of the cell population present in a patient at diagnosis and at relapse.
"When someone comes in and is diagnosed with ALL, [the question is], 'Is every cell the same, or are there subpopulations of cells that might have different genetic alterations?' And does that influence how they behave — more aggressive or less aggressive?" Mullighan asks. His group genetically profiled leukemia patients when they were diagnosed and again later if they relapsed, and found differences in the genetic profiles between the two time points. "Most patients, when they came through the door, had several sets of cells in their body, and some cells would be more resistant to chemotherapy and might come back at the time of relapse," he says.
One recent study that Mullighan published in Nature in collaboration with researchers at the University of Toronto and the Ontario Cancer Institute provides evidence that leukemia-initiating cells branch off into different subclones that can dictate prognosis and treatment outcome. "Some of these changes may only be present at extremely low levels at diagnosis, so one of the challenges we now have is to say at the time of diagnosis, 'Can we find changes in a person at low level, and would that suggest that we change our approach to treatment?'" Mullighan says.
Ultimately, he adds, tests to detect the various subclonal cell types in each patient with leukemia could be useful in the clinic. But first, researchers have to get a better handle on how exactly the intratumoral variances are associated with treatment outcome. Once the changes are fully catalogued, researchers can screen for specific mutations instead of sequencing the whole genome. "I think a very clear implication of this work is that we're now obliged to completely sequence patients that have relapsed leukemia both at diagnosis and relapse to get a full understanding of the genetic changes that are promoting disease relapse," he says.
Researchers also need better technologies to detect these changes at very low levels, Mullighan adds. There are several technologies that exist now — like next-generation sequencing — that can detect structural changes and sequence variance, but the challenge is getting enough coverage and depth at low levels.