Mutations that lead to an impairment of tet methylcytosine dioxygenase 2 (Tet2) function or/and expression – a gene that encodes an epigenetic modifier enzyme – have been related to the development of haematopoietic malignancies in both mice and humans. According to a new study in Nature by Marlies Meisel and Reinhard Hinterleitner from the University of Chicago and collaborators, gut microbiota-dependent signals are critical contributors to a pre-leukemic state in mice that lack Tet2 expression.
Using mice that lack the Tet2 gene, researchers in the lab of Dr. Bana Jabri at the University of Chicago showed that increased small intestinal permeability was present in mice that developed pre-leukemic changes. This disruption of intestinal barrier integrity allowed the translocation of microbes, normally colonizing the small intestine, to tissues beyond the gut. Besides this, an increase in bacteria-induced interleukin (IL)-6, a molecule that promotes inflammation and that is released following systemic bacterial dissemination, was required for the development of the pre-leukemic state in Tet2 deficient mice.
However, antibiotic treatment aborted the pre-leukemic changes, which illustrates the importance of microbial-dependent signals in the development of this condition. Interestingly, once the Tet2 deficient mice were derived and bred in germ-free conditions at the Axenic Gnotobiotic Unit in McMaster University, no changes in IL-6 were observed, and the pre-leukemic state failed to develop. These findings demonstrate the requirement for gut microbiota-dependent inflammatory mediators in the development of pre-leukemic myeloproliferation in mice that lack Tet2 expression.
Mutations or deficiency in the gene Tet2 occur with advancing age and are often present in patients with leukemia. These mutations occur in stem cells that are present in the blood, which are cells that give rise to other blood cells such as white blood cells. The mutations allow the cells to proliferate at a higher rate and increase the risk of developing blood cancers like leukemia. However, only a proportion of individuals with this mutation, or in this study mice that lack Tet2, progress from this stage of increased proliferation to a pre-leukemic state, suggesting that additional environmental factors are needed to drive disease.
“Maintaining intestinal barrier function could be critical for preventing a pre-leukemic state in genetically susceptible people, in order to restrict intestinal microbes to the gut. The study opens the way for potential new strategies aimed at strengthening the intestinal barrier or preventing systemic infections to reduce the progression to leukemia in individuals that have a genetic predisposition”, said Dr. Elena Verdú, co-author of the study and Canada Research Chair in Diet, Microbiota and Intestinal Inflammation.
Meisel M, Hinterleitner R, Pacis A, et al. Microbial signals drive pre-leukaemic myeloproliferation in a Tet2-deficient host. Nature. 2018; doi: 10.1038/s41586-018-0125-z.