Journal
LEUKEMIA RESEARCH
Volume 38, Issue 11, Pages 1332-1341Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.leukres.2014.09.001
Keywords
Acute myeloid leukemia; SGI-110; Cancer testis antigens; Epigenetics; DNA methylation; DNA methyltransferase inhibitors; Cancer germline genes; Immune modulation
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Funding
- Astex Pharmaceuticals
- NCI Cancer Center [CA016056]
- NCI [5T32CA009072-39]
- Roswell Park Alliance Foundation
- Roswell Park Cancer Institute
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The mechanism of clinical action for the FDA approved hypomethylating drugs azacitidine and decitabine remains unresolved and in this context the potential immunomodulatory effect of these agents on leukemic cells is an area of active investigation. Induced expression of methylated Cancer Testis Antigen(CTA) genes has been demonstrated in leukemic cell lines following exposure to hypomethylating drugs in vitro. SGI-110 is a novel hypomethylating dinucleotide with prolonged in vivo exposure and clinical activity in patients with MDS and AML. We demonstrate that this agent, like decitabine, produces robust reexpression of the CTAs NY-ESO-1 and MAGE-A, both in vitro and in leukemia-bearing AML xenografts. Upregulation of these genes in vitro was sufficient to induce cytotoxicity by HLA-compatible CD8+ T-cells specific for NY-ESO-1, a well-recognized and immunogenic CTA. Additionally, exposure to SGI-110 enhances MHC class I and co-stimulatory molecule expression, potentially contributing to recognition of CTAs. SGI-110, like the parent compound decitabine, induces expression of CTAs and might modulate immune recognition of myeloid malignancy. (C) 2014 Elsevier Ltd. All rights reserved.
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