A stem cell mutation that leads to bacterial translocation may help identify patients at risk of developing leukemia.
Bacterial signals play a crucial role in the development of clonal hematopoiesis of indeterminate potential (CHIP), a precursor condition to leukemia, according to a letter published in Nature.
CHIP occurs when there is the development of tet methylcytosine dioxygenas 2 (Tet2) mutations in hematopoietic stem cells, which gives these cells an advantage, so they can proliferate and make up a larger percentage of cells that become white blood cells. This process happens in more than 15% of people older than 60 years.
The researchers found that the progression from CHIP to preleukemic myeloproliferation depends on bacterial signals that spread from the gut to peripheral organs. The study found that defects in the intestinal barrier allowed bacteria in the gut to spread, which, in turn, led to the release of molecules into the blood that set the stage for preleukemic myeloproliferation.
“Years before a patient develops cancer, there are changes happening in the background. They still appear healthy until they reach a tipping point,” Bana Jabri, MD, PhD, professor and vice chair for research in the Department of Medicine at University of Chicago and the senior author of the study, said in a statement. “We have techniques to identify those patients, and now with this paper we know that bacterial signals are key in driving the disease.”
In the study, mice with signs of preleukemic myeloproliferation had gut bacteria in places they shouldn’t be. While there are reasons for intestinal barrier breakdown, the researchers observed no pathogens that cause the type of infection that would disrupt intestinal barrier integrity. As a result, the investigators believe Tet2 mutations caused the dysfunction that allowed gut bacteria to pass through the intestinal barrier.
The findings suggest that potential treatments might be able to limit the risk of developing cancer by reversing preleukemic myeloproliferation. Tet2 mutations and early signs of changes in hematopoietic stem cells can be detected by genetic screening up to 15 years before cancer develops.
Now, studies need to be conducted in humans to see if the same signs of intestinal barrier breakdown and bacterial translocation are occurring in patients with CHIP and preleukemic myeloproliferation.
“This study will prompt new lines of investigation that may profoundly affect the prevention and management of hematopoietic malignancies,” the authors wrote.
Meisel M, Hinterleitner R, Pacis A, et al. Microbial signals drive pre-leukaemic myeloproliferation in a Tet2-deficient host. Nature. 2018;557:580-584. doi: 10.1038/s41586-018-0125-z.