The DNA methyltransferase inhibitors 5-azacitidine (AZA) and 5-aza-2-deoxycytidine (DAC) have been approved for the treatment of higher-risk myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML), and acute myeloid leukemia (AML). A more comprehensive understanding of the molecular changes in patients treated with AZA is needed to help explain why only about 50% of these patients have clinical responses. We examined gene expression profiles in a total of 150 RNA samples taken before, during and after treatment with AZA, in three cohorts of patients with hematological cancers (40 patients total; 15 non-responders, 25 responders). We show that activation of the innate immune system is linked to clinical response to AZA treatment. We also measured the induced expression of transposable elements (TEs) to determine whether this was a potential trigger for the immune response. Both responders and non-responders showed robust upregulation of TEs however responders showed the statistically significant upregulation of specific classes of evolutionarily young transposable elements (TEs). These include short and long nuclear elements (SINEs and LINEs) and endogenous retroviruses (ERVs). Moreover, the upregulation of type I interferon signaling pathway genes in responders was significantly higher than non-responders, but not cancer testis antigens (CTAs) or tumor suppressor genes with the exception of CDKN2A and CDKN2B. Therefore, we suggest that induction of specific subsets of silenced evolutionarily young TEs may be a key to the success of epigenetic therapy in hematological cancer patients.

Citation Format: Hitoshi Ohtani, Andreas D. Ørskov, Alexandra S. Helbo, Linn Gillberg, Minmin Liu, Wanding Zhou, Johanna Ungerstedt, Eva Hellstrom-Lindberg, Weili Sun, Gangning Liang, Peter A. Jones, Kirsten Grønbæk. Activation of evolutionarily young transposable elements and the host innate immune system are linked to clinical response to 5-azacitidine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3092.