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DNMTi Decitabine Induces a Type I Interferon Response in Leukemia Cell Lines
Author(s) -
Nicholas David J,
Srivastava Pragya,
AlShangity AlMujtaba,
Nemeth Michael J
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.595.16
Subject(s) - cancer research , decitabine , interferon , myeloid leukemia , isg15 , hl60 , biology , downregulation and upregulation , leukemia , azacitidine , k562 cells , cell culture , immunology , gene expression , dna methylation , biochemistry , genetics , gene , ubiquitin
Decitabine (DAC) is an FDA approved DNA methyltransferase inhibitor (DNMTi) currently used for treatment of Myelodysplastic Syndrome and Acute Myeloid Leukemia. Only 40% of patients respond to DAC treatment. Therefore, discovering and enhancing DAC's mechanism of action is of paramount importance. Recent literature suggests that DNMTis demethylate and induce expression of latent dsRNA retroviral species in ovarian cancer and colorectal cell lines. This viral mimicry triggers an interferon response that results in both apoptosis and targeting of treated cancer cells. To test whether a similar mechanism of action occurs in myeloid cancer, the leukemia cell lines U937, HL60, and KG1a were evaluated for gene expression changes in the interferon response pathway after two treatments of 0.5um DAC using RTqPCR. Up regulation of Interferon response genes DDX58, MDA5, OASL, MAVS, ISG15, IFN B , and IRF7 were observed in KG1a cells with reported fold changes of 3.45, 1.88, 54.40, 2.04, 3.25, 5.88, and 80.00 respectively. In addition, the ERV MLT1C49 was upregulated by a fold change of 2.46. In the U937 cell line , DDX58, MDA5, OASL, MAVS , and ISG15 , were upregulated by 1.59, 2.02, 3.62, 1.468, and 6.3646, respectively. For the HL60 cell line, DDX58, OASL, and ISG15 were upregulated by 1.79, 5.16, and 1.87, respectively. In summary, our data suggests Decitabine induces a type I interferon response in leukemia cells, giving promise to the combinatorial treatment of DAC with emerging immunotherapy treatments. Support or Funding Information NIH R25CA181003 and SUNY Geneseo Biology Department