Pluto Bioinformatics

GSE99333: Bacterial translocation is required for pre-leukemic myeloproliferation in Tet2 deficient mice

Bulk RNA sequencing

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. SOURCE: Alain Pacis (vapacis@gmail.com) - Barreiro Lab CHU Ste-Justine