Microbial Signals Promote Preleukemic Myeloproliferation in Tet2^−/− Mice

Mutations in TET2, which promotes DNA demethylation by converting 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), can drive the development of hematopoietic malignancies. However, TET2 mutation is not sufficient to drive preleukemic myeloproliferation (PMP), suggesting that cell-extrinsic factors are required to induce malignancy. Meisel, Hinterleitner, and colleagues sought to identify factors that cooperate with TET2 mutation to promote PMP. Tet2^−/− mice had increased systemic bacterial dissemination that was associated with increased intestinal permeability and PMP, suggesting that disrupting intestinal barrier integrity may induce PMP in Tet2^−/− mice. Consistent with these findings, Lactobacillus species normally found in the small intestine were detected predominantly in the peripheral organs of Tet2^−/− mice. TLR2 is a cell wall component of several Lactobacillus strains, and using TLR2 agonists to mimic bacterial stimuli resulted in PMP induction in Tet2^−/− mice. In germ-free conditions, Tet2^−/− mice failed to develop PMP. Further, antibiotic treatment was sufficient to prevent and reverse PMP, directly linking PMP to bacterial signals. A microbiota-dependent increase in IL6 plasma levels, which led to an expansion of IL6Rα⁺ granulocyte-macrophage progenitors, occurred in Tet2^−/− mice and was required for the induction of PMP. Neutralizing IL6 suppressed the self-renewing capacity of Tet2^−/− hematopoietic progenitor cells and prevented PMP development in vivo without restoring intestinal barrier function. Taken together, these findings suggest that microbial-dependent inflammatory signals induce PMP development in the context of TET2-deficiency. Further, these data raise the possibility of targeting inflammatory bacterial signals in patients with TET2-deficient PMP to suppress the progression to hematopoietic malignancy.

Meisel M, Hinterleitner R, Pacis A, Chen L, Earley ZM, Mayassi T, et al. Microbial signals drive pre-leukaemic myeloproliferation in a Tet2-deficient host. Nature 2018;557:580–4.

Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.