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

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. Normal Tet2KO CD4+ T cells and lymphoma cells were isolated from Tet2 deficient mouse model to identify the differential expressed genes. Tet2KO lymphoma mouse and CMML mouse were treated with and without antibiotics cocktail (ABX). Cells were isolated from these groups to identify the differential expressed genes between ABX treated and untreated groups. Third-party re-analysis: LK1 (GSM1902319) and LK2 (GSM1902320) processed data are represented in LK_KO-Tet2KO_CMML_vehicle-Tet2KO_CD4_Tcell-Tet2KO_lymphoma.normalized.txt.