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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE99333 | GEO | 2018/03/15

REPOSITORIES: GEO

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Project description:TET2 is a close relative of TET1, an enzyme that converts 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) in DNA. The gene encoding TET2 resides at chromosome 4q24, in a region showing recurrent microdeletions and copy-neutral loss of heterozygosity (CN-LOH) in patients with diverse myeloid malignancies. Somatic TET2 mutations are frequently observed in myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), MDS/MPN overlap syndromes including chronic myelomonocytic leukaemia (CMML), acute myeloid leukaemias (AML) and secondary AML (sAML). We show here that TET2 mutations associated with myeloid malignancies compromise catalytic activity. Bone marrow samples from patients with TET2 mutations displayed uniformly low levels of 5hmC in genomic DNA compared to bone marrow samples from healthy controls. Moreover, small hairpin RNA (shRNA)-mediated depletion of Tet2 in mouse haematopoietic precursors skewed their differentiation towards monocyte/macrophage lineages in culture. There was no significant difference in DNA methylation between bone marrow samples from patients with high 5hmC versus healthy controls, but samples from patients with low 5hmC showed hypomethylation relative to controls at the majority of differentially methylated CpG sites. Our results demonstrate that Tet2 is important for normal myelopoiesis, and suggest that disruption of TET2 enzymatic activity favours myeloid tumorigenesis. Measurement of 5hmC levels in myeloid malignancies may prove valuable as a diagnostic and prognostic tool, to tailor therapies and assess responses to anticancer drugs. Genome wide DNA methylation profiling of patients samples with various myeloid malignancies and diffrential levels of 5hmC.The Illumina Infinium 27k Human DNA methylation Beadchip v1.2 was used to obtain DNA methylation profiles across approximately 27,000 CpGs in bone marrow samples and occasionally peripheral blood samples. Samples included 28 control healthy bone marrows, 29 patients samples with low 5hmC levels (7 patients with wild-type TET2 and 22 mutant TET2) and 24 with high levels of 5hmC (22 with wild-type TET2 and 2 mutant TET2). Bisulphite converted DNA from 81 samples was hybridised to the Illumina Infinium 27k Human Methylation Beadchip v1.2

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

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