@article{b3cdbc99ea224a71af23f96d88aed0e7,
title = "Immunomodulatory action of SGI-110, a hypomethylating agent, in acute myeloid leukemia cells and xenografts",
abstract = "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 re-expression 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.",
keywords = "Acute myeloid leukemia, Cancer germline genes, Cancer testis antigens, DNA methylation, DNA methyltransferase inhibitors, Epigenetics, Immune modulation, SGI-110",
author = "Pragya Srivastava and Paluch, {Benjamin E.} and Junko Matsuzaki and James, {Smitha R.} and Golda Collamat-Lai and Julia Karbach and Nemeth, {Michael J.} and Pietro Taverna and Karpf, {Adam R.} and Griffiths, {Elizabeth A.}",
note = "Funding Information: The authors would like to thank Drs. Kunle Odunsi and Mohammad Azab for the intellectual support of this project and Dr. Michael Moser from the animal core facility at Roswell Park Cancer Institute. EAG and ARK designed the research study; PS, BEP, JM, SRJ, GCL and JK performed the research; EAG, ARK, PS, JM and MJN analyzed the data; PT contributed essential reagents and helped to design the mouse experiments; PS, BEP, EAG and ARK wrote the paper. This work was funded by a research grant from Astex Pharmaceuticals (to EAG and ARK) and by the NCI Cancer Center Support Grant CA016056 . BEP was supported through an institutional training grant from the NCI ( 5T32CA009072-39 ). EAG and MJN are supported by the Roswell Park Alliance Foundation and by institutional funds provided by Roswell Park Cancer Institute. Funding Information: EAG and ARK declare that funding for this work was provided through a research grant from Astex Pharmaceuticals, we therefore declare this as a conflict of interest. PT is an employee of Astex Pharmaceuticals and declares this as a conflict of interest, PS, BEP, JM, GCL, SRJ, JK, MJN have no conflicts to disclose. Publisher Copyright: {\textcopyright} 2014 Elsevier Ltd.",
year = "2014",
month = nov,
day = "1",
doi = "10.1016/j.leukres.2014.09.001",
language = "English (US)",
volume = "38",
pages = "1332--1341",
journal = "Leukemia Research",
issn = "0145-2126",
publisher = "Elsevier Limited",
number = "11",
}