Bacterial translocation is required for pre-leukemic myeloproliferation in Tet2 deficient mice

Ten-Eleven-translocation (Tet2) encodes an epigenetic modifier enzyme and is mutated somatically during age-associated clonal hematopoiesis of indeterminate potential (CHIP) as well as in myeloid malignancies 1-7. Tet2 deficiency leads to increased hematopoietic stem cell (HSC) renewal in human 7 and mouse 8. However, the development of myeloproliferation and myeloid malignancies occurs at late age, and only occasionally in humans 2,6,7,9 and in 50-75% of Tet2 deficient animals 8,10,11, suggesting that undefined triggers are required for pre-leukemic myeloid expansion. Our studies reveal that Tet2 deficient mice can exhibit high levels of plasma IL-6, systemic dissemination of indigenous gut bacteria and increased intestinal permeability that correlate with the development of a pre-leukemic myeloproliferative phenotype. Increased intestinal permeability was linked to a large number of transcriptional changes in the jejunum, especially among genes involved in defense response to bacterium and intestinal barrier function. Strikingly, antibiotic treatment reduced plasma IL-6 levels and both, prevented early myeloid expansion and reversed the pre-leukemic myeloproliferative phenotype in Tet2-/- mice. In summary, we show that Tet2 deficiency promotes intestinal bacterial translocation and subsequent systemic inflammation, and that gut-derived microbial signals are required for the development of pre-leukemic myeloproliferation in a Tet2-deficient host. Our studies suggest that controlling bacterial translocation and bacteria-associated systemic inflammation could decrease the risk of myeloid malignancies significantly in individuals with somatic Tet2 mutations. Expression profiles in intestinal tissues from WT and TET2KO mice, before and after ABX treatment