Silencing of retrotransposons by SET DB1 inhibits the interferon response in acute myeloid leukemia

L. Cuellar, Anna Maria Herzner, Xiaotian Zhang, Yogesh Goyal, Colin Watanabe, Brad A. Friedman, Vasantharajan Janakiraman, Steffen Durinck, Jeremy Stinson, David Arnott, Tommy K. Cheung, Subhra Chaudhuri, Zora Modrusan, Jonas Martin Doerr, Marie Classon, Benjamin Haley*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

76 Scopus citations

Abstract

A propensity for rewiring genetic and epigenetic regulatory networks, thus enabling sustained cell proliferation, suppression of apoptosis, and the ability to evade the immune system, is vital to cancer cell propagation. An increased understanding of how this is achieved is critical for identifying or improving therapeutic interventions. In this study, using acute myeloid leukemia (AML) human cell lines and a custom CRI SPR/Cas9 screening platform, we identify the H3K9 methyltransferase SET DB1 as a novel, negative regulator of innate immunity. SET DB1 is overexpressed in many cancers, and loss of this gene in AML cells triggers desilencing of retrotransposable elements that leads to the production of double- stranded RNAs (dsRNAs). This is coincident with induction of a type I interferon response and apoptosis through the dsRNA-sensing pathway. Collectively, our findings establish a unique gene regulatory axis that cancer cells can exploit to circumvent the immune system.

Original languageEnglish (US)
Pages (from-to)3535-3549
Number of pages15
JournalJournal of Cell Biology
Volume216
Issue number11
DOIs
StatePublished - Nov 1 2017
Externally publishedYes

ASJC Scopus subject areas

  • Cell Biology

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