Under certain conditions, bacterial signals set the stage for leukemia

A new study by researchers from the University of Chicago Medicine shows that bacterial signals are crucial to the development of a precursor condition to leukemia, which can be induced by disrupting the intestinal barrier or by introducing a bacterial infection.

More than 15 percent of people over the age of 60 develop TET2 (tet methylcytosine dioxygenase 2) mutations in hematopoietic stem cells, which give rise to other blood cells. These are known as somatic mutations because they are not inherited, but instead occur by chance with age. These mutations are passed along to the progeny of the mutated cell during cell division and put these patients at risk for blood cancers.

The TET2 mutation gives the hematopoietic stem cells a competitive advantage over others, so they begin to proliferate and make up a greater percentage of cells that become white blood cells. This is a condition known as Clonal Hematopoiesis of Indeterminate Potential, or CHIP. However, the triggers that lead to the progression from CHIP to a precursor condition to leukemia called pre-leukemic myeloproliferation are unknown.

The new study, published May 16, 2018 in Nature, shows that progression from CHIP to pre-leukemic myeloproliferation is dependent on bacterial signals from bacteria normally present in the gut that spread to peripheral organs. The authors studied Tet2-deficient mice, which were shown to develop leukemia with age. However, why only a subset of these mice develop leukemia was not understood.

The study demonstrated that loss of TET2 expression leads to defects in the intestinal barrier, allowing bacteria living in the gut to spread into the blood and peripheral organs. The spread of bacteria leads to the release of inflammatory molecules in the blood, which in turn promote the proliferation of hematopoietic stem cells that lack TET2 expression. This sets the stage for pre-leukemic myeloproliferation.

“Years before a patient develops cancer, there are changes happening in the background. They still appear healthy until they reach a tipping point,” said Bana Jabri, MD, PhD, professor and vice chair for research in the Department of Medicine at UChicago and the senior author of the study. “We have techniques to identify those patients, and now with this paper we know that bacterial signals are key in driving the disease.”