Activation of a Subset of Evolutionarily Young Transposable Elements and Innate Immunity Are Linked to Clinical Responses to 5-Azacytidine
- 3 April 2020
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 80 (12), 2441-2450
- https://doi.org/10.1158/0008-5472.can-19-1696
Abstract
The DNA methyltransferase inhibitors (DNMTi) 5-azacytidine (AZA) and 5-aza-2-deoxycytidine have been approved for the treatment of different types of hematological malignancies. However, only about 50% of patients respond to treatment. Therefore, a more comprehensive understanding of the molecular changes in patients treated with DNMTi is needed. Here we examined gene expression profiles in a total of 150 RNA samples from two adult cohorts and one pediatric cohort with hematological cancers taken before, during, and after treatment with AZA (40 patients; 15 non-responders, 25 responders). Using each patient as their own control, malignant cells showed preferential activation of a subset of evolutionarily young transposable elements (TE), including endogenous retroviral long terminal repeats (LTR), short and long interspersed nuclear elements (SINE and LINE), and the type I interferon (IFN) pathway in responders, all independent of disease classification. Transfection of eight upregulated LTR into recipient human cells in culture showed robust and heterogenous activation of six genes in the type I IFN pathway. These results, obtained in diverse hematological disease entities, show that common targets (TE) activated by the same drug (AZA) elicit an immune response which may be important for patient's responses to DNMTi.Other Versions
Funding Information
- NCI (R35CA209859)
- Lundbeck Foundation (R180-2014-3675)
- Danish Cancer Society (R124-A7695)
- Novo Nordisk Foundation (NNF13OC0003435)
- Danish Research Center (223-A13071-18-S68)
- Novo Nordisk Foundation (NNF17CC0027852)
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