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.
authors.affiliation: Department of Medicine, Roswell Park Cancer Institute, Elm & Carlton Sts, Buffalo, NY 14263, USA.
authors.forename: Pragya
authors.initials: P
authors.lastname: Srivastava
authors.affiliation: Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm & Carlton Sts, Buffalo, NY 14263, USA.
authors.forename: Benjamin E
authors.initials: BE
authors.lastname: Paluch
authors.affiliation: Center for Immunotherapy, Roswell Park Cancer Institute, Elm & Carlton Sts, Buffalo, NY 14263, USA.
authors.forename: Junko
authors.initials: J
authors.lastname: Matsuzaki
authors.affiliation: Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm & Carlton Sts, Buffalo, NY 14263, USA.
authors.forename: Smitha R
authors.initials: SR
authors.lastname: James
authors.affiliation: Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm & Carlton Sts, Buffalo, NY 14263, USA.
authors.forename: Golda
authors.initials: G
authors.lastname: Collamat-Lai
authors.affiliation: Klinik für Onkologie und Hämatologie, Krankenhaus Nordwest, Frankfurt, Steinbacher Hohl 2-26, 60488 Frankfurt, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Karbach
authors.affiliation: Department of Medicine, Roswell Park Cancer Institute, Elm & Carlton Sts, Buffalo, NY 14263, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Nemeth
authors.affiliation: Astex Pharmaceuticals, Inc., 4140 Dublin Blvd., Suite 200, Dublin, CA 94568, USA.
authors.forename: Pietro
authors.initials: P
authors.lastname: Taverna
authors.affiliation: Eppley Institute, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198-5950, USA. Electronic address: adam.karpf@unmc.edu.
authors.forename: Adam R
authors.initials: AR
authors.lastname: Karpf
authors.affiliation: Department of Medicine, Roswell Park Cancer Institute, Elm & Carlton Sts, Buffalo, NY 14263, USA. Electronic address: elizabeth.griffiths@roswellpark.org.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Griffiths
mesh_terms: D000818:Animals; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D019175:DNA Methylation; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology*; D015470:Leukemia, Myeloid, Acute / Q000473:pathology*; D051379:Mice; D016513:Mice, SCID; D020133:Reverse Transcriptase Polymerase Chain Reaction; D023041:Xenograft Model Antitumor Assays
chemical_list: D007155:Immunologic Factors; C580831:guadecitabine; D001374:Azacitidine
keywords: Acute myeloid leukemia; Cancer germline genes; Cancer testis antigens; DNA methylation; DNA methyltransferase inhibitors; Epigenetics; Immune modulation; SGI-110