Abstract 6320: Connecting TET2 deficiency with inflammation in CMML and anti-tumor responses

Abstract

Abstract Chronic Myelomonocytic Leukemia (CMML) is a clonal hematologic disorder of older individuals characterized by monocytosis and increased risk of progression to acute myeloid leukemia (AML). Although CMML is characterized by relatively low genetic complexity consistent with clonal expansion, loss-of-function mutations in ten-eleven translocation 2 (TET2) protein are frequent and reported in almost 60% of CMML cases. Consistent with this finding, deletion of the Tet2 gene in mice leads to CMML-like disease. TET2 restrains inflammatory signals through various means, for instance by directly suppressing the expression of the IL6 gene in mouse myeloid cells by recruiting histone deacetylases. Conversely, the levels of pre-inflammatory cytokines including IL6 correlate with pre-leukemic proliferation of Tet2-deficient mouse monocytes and other myeloid cells, suggesting that Tet2 deficiency increases IL-6 expression and increased IL-6 expression in turn drives the proliferation of Tet2-deficient myeloid-lineage cells in a positive feedback loop. This scenario may operate in CMML patients, who show increased levels of inflammatory cytokines and increased expression of interferon-induced genes compared to age-matched healthy individuals. To gain insight into the connection between inflammation caused by TET deficiency and monocyte hyperproliferation, we set up cultures of bone marrow derived macrophages (BMDMs) from inducible TET deficient mice. Using this model, we found that TET-deficient BMDMs show increased proliferation compared to wild type controls; moreover, LPS stimulation leads to significantly increased expression of IL6 and IL1b in TET-deficient BMDMs. Our previous RNA sequencing of expanded TET-deficient myeloid cells in vivo showed that TET deficiency correlated with increased expression of transposable elements (TEs) and induced a DNA damage response, leading us to hypothesize that TET deficiency and increased TE expression may activate DNA and RNA sensing pathways and induce sterile inflammation. I am currently using several molecular approaches to delineate the potential connection of TET deficiency with endogenous inflammation in CMML. There is growing evidence that TET deficiency or non-specific inhibition of TET enzymes in CD8 T cells can potentiate anti-tumor responses. I am now asking whether the TET deficiency-inflammation axis I observe in BMDMs might also enhance anti-tumor responses by increasing proinflammatory responses and hence T cell recruitment and anti-tumor activity. Citation Format: Anup Kumar Singh, Atsushi Onodera, Hugo Sepulveda, Carlos Angel, Anjana Rao. Connecting TET2 deficiency with inflammation in CMML and anti-tumor responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6320.