Activation of a Subset of Evolutionarily Young Transposable Elements and Innate Immunity Are Linked to Clinical Responses to 5-Azacytidine.

Abstract

The DNA methyltransferase inhibitors (DNMTi) 5-azacytidine and 5-aza-2-deoxycytidine have been approved for the treatment of different types of hematologic 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 hematologic cancers taken before, during, and after treatment with 5-azacytidine (40 patients; 15 nonresponders, 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 IFN pathway in responders, all independent of disease classification. Transfection of eight upregulated LTRs 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 hematologic disease entities, show that common targets (TE) activated by the same drug (5-azacytidine) elicit an immune response, which may be important for patient's responses to DNMTi. SIGNIFICANCE: Activation of specific classes of evolutionarily young transposable elements can lead to activation of the innate immune system.

• Authors: Hitoshi Ohtani, Andreas D Ørskov, Alexandra S Helbo, Linn Gillberg, Minmin Liu, Wanding Zhou, Johanna Ungerstedt, Eva Hellström-Lindberg, Weili Sun, Gangning Liang, Peter A Jones, Kirsten Grønbæk
• Journal: Cancer research (Cancer Res) Vol. 80 Issue 12 Pg. 2441-2450 (06 15 2020) ISSN: 1538-7445 [Electronic] United States
• PMID: 32245794 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2020 American Association for Cancer Research.

Chemical References

• Antimetabolites, Antineoplastic
• DNA Transposable Elements
• Interferon Type I
• Azacitidine

Topics

• Aged
• Aged, 80 and over
• Antimetabolites, Antineoplastic (pharmacology, therapeutic use)
• Azacitidine (pharmacology, therapeutic use)
• Cohort Studies
• DNA Transposable Elements (drug effects, genetics)
• Drug Resistance, Neoplasm (genetics, immunology)
• Endogenous Retroviruses (genetics)
• Female
• Gene Expression Regulation, Neoplastic (drug effects, immunology)
• Hematologic Neoplasms (drug therapy, genetics, immunology)
• Humans
• Immunity, Innate (drug effects, genetics)
• Interferon Type I (metabolism)
• Male
• Middle Aged
• Molecular Mimicry (immunology)
• RNA-Seq
• Signal Transduction (drug effects, genetics, immunology)
• Up-Regulation (drug effects)