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Antibiotics treatment ameliorates TET2 loss-of-function associated hematological malignancies

ABSTRACT: TET2 is one of the most frequently mutated genes in hematological malignancies. TET2 mutations are also frequently observed in healthy individuals with clonal hematopoiesis. Additional factors, such as inflammatory stress, might promote the expansion and initiate the pre-leukemic condition of Tet2 deficient hematopoietic stem cells. Antibiotics treatment is frequently used in normal individuals and patients with hematological malignancies treatment to suppress infection-induced inflammation. However, prolonged antibiotics treatment resulted in bone marrow suppression and gut microbiota alteration. In our study, we observed that the expansion of Tet2 deficient myeloid cells are positively correlated with serum cytokine levels at pre-malignant stages. We then evaluated the effect of antibiotic treatment in Tet2 deficient myeloid and lymphoid tumors in vivo. We found that antibiotics treatment suppressed the growth of Tet2 deficient malignant cells in vivo. RNA-seq analysis revealed significant changes in immune related signaling pathways (e.g., Tnf-α signaling) in antibiotics treated Tet2 deficient myeloid and lymphoid tumor cells. Suppression of Tnf-α signaling using pharmacological inhibitors partially suppressed Tet2 deficient tumor cell growth in vivo. In summary, our results suggest that the expansion of Tet2 deficient blood cells are positively associated with a pre-inflammatory condition and suppression of inflammatory pathways may attenuate the progression of TET2 inactivation-associated hematological malignancies.

ORGANISM(S): Mus musculus

PROVIDER: GSE129886 | GEO | 2021/04/01

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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Antibiotics treatment ameliorates TET2 loss-of-function associated hematological malignancies

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