Antibiotic treatment ameliorates Ten-eleven translocation 2 (TET2) loss-of-function associated hematological malignancies. (28th December 2019)

• Record Type: Journal Article
• Authors: Zeng, Hongxiang; He, Hailan; Guo, Lei; Li, Jia; Lee, Minjung; Han, Wei; Guzman, Anna G.; Zang, Shengbing; Zhou, Yubin; Zhang, Xiaotian; Goodell, Margaret A.; King, Katherine Y.; Sun, Deqiang; Huang, Yun
• Is Part Of: Cancer letters. Volume 467(2019)
• Page Start: 1
• Page End: 8
• Publication Date: 2019-12-28
• Subjects: Epigenetics -- TET2 -- Hematological malignancies -- Inflammation -- Antibiotics; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2019.09.013
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: TET2 is among the most frequently mutated genes in hematological malignancies, as well as in healthy individuals with clonal hematopoiesis. Inflammatory stress is known to promote the expansion of Tet2 -deficient hematopoietic stem cells, as well as the initiation of pre-leukemic conditions. Infection is one of the most frequent complications in hematological malignancies and antibiotics are commonly used to suppress infection-induced inflammation, but their application in TET2 mutation-associated cancers remained underexplored. In this study, we discovered that Tet2 depletion led to aberrant expansion of myeloid cells, which was correlated with elevated serum levels of pro-inflammatory cytokines at the pre-malignant stage. Antibiotics treatment suppressed the growth of Tet2- deficient myeloid and lymphoid tumor cells in vivo . Transcriptomic profiling further revealed significant changes in the expression of genes involved in the TNF-α signaling and other immunomodulatory pathways in antibiotics-treated tumor cells. Pharmacological inhibition of TNF-α signaling partially attenuated Tet2 -deficient tumor cell growth in vivo . Therefore, our findings establish the feasibility of targeting pro-inflammatory pathways to curtail TET2 inactivation-associated hematological malignancies. Highlights: Variegated hematological malignant phenotypes were observed in aged Tet2-deficient mice. Serum cytokine production is positively correlated with myeloid expansion in Tet2KO mice. Antibiotics treatment suppresses the growth of Tet2-deficient hematological malignancies in vivo . The suppressive effect of antibiotics on Tet2-deficient neoplasms is partially mediated by inhibiting TNF signaling.