title: Cancer-testis antigen expression and its epigenetic modulation in acute myeloid leukemia.
abstract: Cancer-testis antigens (CTA) represent attractive targets for tumor immunotherapy. However, a broad picture of CTA expression in acute myeloid leukemia (AML) is missing. CTA expression was analyzed in normal bone marrow (BM) as well as in AML cell lines before and after treatment with demethylating agents and/or histone acetylase inhibitors. Presence of selected CTA with a strictly tumor-restricted expression was then determined in samples of patients with AML before and after demethylating therapy. Screening AML cell lines for the expression of 20 CTA, we identified six genes (MAGE-A3, PRAME, ROPN1, SCP-1, SLLP1, and SPO11) with an AML-restricted expression. Analyzing the expression of these CTA in blast-containing samples from AML patients (N = 64), we found all samples to be negative for MAGE-A3 and SPO11 while a minority of patients expressed ROPN1 (1.6%), SCP-1 (3.1%), or SLLP1 (9.4%). The only CTA expressed in substantial proportion of patients (53.1%) was PRAME. Following demethylating treatment with 5'-aza-2'-deoxycytidine, we observed an increased or de novo expression of CTA, in particular of SSX-2, in AML cell lines. In AML patients, we detected increased expression of PRAME and induction of SSX-2 after demethylating therapy with 5-azacytidine. With the exception of PRAME, CTA are mostly absent from AML blasts. However, demethylating treatment induces strong expression of CTA, particularly of SSX-2, in vitro and in vivo. Therefore, we propose that CTA-specific immunotherapy for AML should preferentially target PRAME and/or should be combined with the application of demethylating agents opening the perspective for alternative targets like CTA SSX-2.
authors: Center of Oncology, Department of Internal Medicine II, Oncology/Hematology/Stem Cell Transplantation, University Cancer Center Hamburg, Germany. D.Atanackovic@uke.uni-hamburg.de
authors: Djordje
authors: D
authors: Atanackovic
authors: Tim
authors: T
authors: Luetkens
authors: Benjamin
authors: B
authors: Kloth
authors: Gregor
authors: G
authors: Fuchs
authors: Yanran
authors: Y
authors: Cao
authors: York
authors: Y
authors: Hildebrandt
authors: Sabrina
authors: S
authors: Meyer
authors: Katrin
authors: K
authors: Bartels
authors: Henrike
authors: H
authors: Reinhard
authors: Nesrine
authors: N
authors: Lajmi
authors: Susanna
authors: S
authors: Hegewisch-Becker
authors: Georgia
authors: G
authors: Schilling
authors: Uwe
authors: U
authors: Platzbecker
authors: Guido
authors: G
authors: Kobbe
authors: Thomas
authors: T
authors: Schroeder
authors: Carsten
authors: C
authors: Bokemeyer
authors: Nicolaus
authors: N
authors: Kröger
mesh_terms: D000368:Aged; D000951:Antigens, Neoplasm / Q000235:genetics* / Q000378:metabolism; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015415:Biomarkers / Q000032:analysis; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D019175:DNA Methylation; D000077209:Decitabine; D057890:Epigenomics; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D056572:Histone Deacetylase Inhibitors / Q000009:adverse effects / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000009:adverse effects / Q000494:pharmacology*; D007167:Immunotherapy / Q000379:methods; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation
chemical_list: D000951:Antigens, Neoplasm; D000964:Antimetabolites, Antineoplastic; D015415:Biomarkers; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D009363:Neoplasm Proteins; C404944:PRAME protein, human; D012097:Repressor Proteins; C093962:synovial sarcoma X breakpoint proteins; C012589:trichostatin A; D000077209:Decitabine; D006655:Histone Deacetylases; D001374:Azacitidine