Expression, epigenetic regulation, and humoral immunogenicity of cancer-testis antigens in chronic myeloid leukemia

Luetkens, Tim; Schafhausen, Phillipe; Uhlich, Frederike; Stasche, Tim; Akbulak, Ruken Ö.; Bartels, Britta Marlen; Hildebrandt, York; Gontarewicz, Arthur; Kobold, Sebastian; Meyer, Scott C.; Gordic, Maja; Bartels, Katrin; Lajmi, Nesrine; Cao, Yanran; Kröger, Nicolaus; Bokemeyer, Carsten; Brümmendorf, Tim H.; Atanackovic, Djordje

doi:10.1016/j.leukres.2010.03.039

Cited by 32 publications

(24 citation statements)

References 54 publications

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“…PRAME, which was first described in 1997 by Ikeda et al [36], has previously been shown to be expressed in 35-64% of AML patients [29,30,[37][38][39]. On the other hand, we have shown here that PRAME is absent from non-malignant hematopoetic cells, which is in line with our previous analysis of a panel of 23 healthy tissues including PBMC, BM samples, and CD341 progenitor cells from healthy donors [16]. We propose that PRAME's expression pattern and ability to elicit significant cellular immune responses in vitro [40] and in vivo [36] make it a prime target for antigen-specific immunotherapies of AML.…”

Section: Discussionsupporting

confidence: 91%

“…To assess the influence of treatment with epigenetic agents on CTA expression by AML blasts, cell lines were treated with 1 lM of demethylating agent 5 0 -aza-2 0 -deoxycytidine (Decitabine; Sigma-Aldrich, St. Louis, MO) and/or 5 lM of HDAC inhibitor trichostatin A (Sigma-Aldrich). These are standard concentrations for the in vitro treatment of tumor cell lines [15], and we have previously applied the same concentrations of both reagents to promote CTA expression, that is, in chronic myeloid leukemia (CML) cell lines [16]. Expression of CTA was evaluated in untreated cell lines and following 24-hr stimulation with the respective epigenetic agents.…”

Section: Methodsmentioning

confidence: 99%

“…Reverse transcription PCR (RT-PCR) was performed as described previously [16]. PCR primer sequences and conditions used for the analysis are given in Supporting Information Table 1.…”

Section: Methodsmentioning

confidence: 99%

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Cancer‐testis antigen expression and its epigenetic modulation in acute myeloid leukemia

et al. 2011

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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 5 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 0 -aza-2 0 -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. Am. J. Hematol. 86:918-922, 2011. V

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Section: Discussionsupporting

confidence: 91%

Section: Methodsmentioning

confidence: 99%

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Cancer‐testis antigen expression and its epigenetic modulation in acute myeloid leukemia

et al. 2011

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“…Ikeda et al (1) first identified the antigen PRAME and revealed that the demethylating agent 5-aza-2'-deoxycytidine could activate PRAME gene expression, which implied that DNA methylation was involved in the regulation of its expression. Subsequent studies confirmed this result in AML and chronic myeloid leukemia (CML) (17)(18)(19)(20)(21)(22). However, despite numerous studies demonstrating an inverse correlation between methylation of specific 5'-C-phosphate-G-3' (CpG) sites and PRAME expression, the CpG island regions studied were different (17)(18)(19)(20).…”

Section: Introductionmentioning

confidence: 95%

Methylation pattern of preferentially expressed antigen of melanoma in acute myeloid leukemia and myelodysplastic syndromes

et al. 2017

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Abstract. Preferentially expressed antigen of melanoma (PRAME), a tumor-associated antigen, is overexpressed in a variety of hematologic malignancies with a great variation in expression. The majority of patients with acute myeloid leukemia (AML) 1-eight-twenty one (ETO) + AML and a certain number of myelodysplastic syndromes (MDS) have an abnormally high increase in PRAME expression level. The landscape of PRAME methylation requires evaluation in order to determine the most relevant sites and the exact association of its methylation with expression level and type of disease. In the present study, bone marrow samples collected from 8 AML1-ETO + AML, 4 MDS, 3 AML1-ETO -AML and 2 normal volunteers underwent bisulfate sequencing to analyze the methylation status of all four 5'-C-phosphate-G-3' (CpG) regions within the entire PRAME gene. The median PRAME transcript level of 15 patients was 204.5% (range, 0.02-710.3%). PRAME transcript levels were inversely associated with the degree of methylation of the -389 to -146 CpG sites (r=-0.69; P=0.002) in the 3' part of the promoter region and the +132 to +363 CpG sites (r=-0.69; P=0.006) in the exon 1b region. However, not every sample strictly followed this correlation: Certain samples with high degrees of methylation demonstrated abnormally high expression levels, and vice versa. The methylation ratios of CpG sites in exon 1a were low for all samples (range, 0.0-13.8%), and those in exon 2 were similar in 16 samples (range, 72.4-93.4%), with the exception of one patient with high expression (425.2%) and significantly low degree of methylation in the PRAME gene (22.2%). MDS patients revealed similar methylation ratios in the 3' section of the promoter region, but tended to have lower methylation ratios in the exon 1b region (P=0.62 and P=0.09, respectively) compared with those observed in AML1-ETO + patients with AML and similar degree of PRAME overexpression. Therefore, the hypomethylation of CpG sites in the 3' part of the promoter region and in exon 1b was typically found with PRAME overexpression in AML and MDS. Methylation of other CpG islands, epigenetic and genetic mechanisms, and type of disease may also be involved.

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“…24 Hepatitis B virus core antigen (FLPSDFPSV residues 18-27; referred as the FL peptide) was used as the positive standard for high HLA-A*0201-binding affinity. 24 Immunofluorescence PRAME expression was evaluated at the subcellular level with an immunofluorescence assay, as described previously 25 with some modifications. Briefly, 5 ϫ 10 4 MNCs derived from 3 bone marrow and 2 peripheral blood samples from patients with CML were suspended in PBS and centrifuged on a glass slide using a Shandon CytoSpin 2 (ThermoFisher Scientific).…”

Section: Hla Peptide-binding Assaymentioning

confidence: 99%

High-avidity cytotoxic T lymphocytes specific for a new PRAME-derived peptide can target leukemic and leukemic-precursor cells

Quintarelli

Dotti

Hasan

et al. 2011

Blood

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The cancer testis antigen (CTA) preferentially expressed antigen of melanoma (PRAME) is overexpressed by many hematologic malignancies, but is absent on normal tissues, including hematopoietic progenitor cells, and may therefore be an appropriate candidate for T cellmediated immunotherapy. Because it is likely that an effective antitumor response will require high-avidity, PRAMEspecific cytotoxic T lymphocytes (CTLs), we attempted to generate such CTLs using professional and artificial antigenpresenting cells loaded with a peptide library spanning the entire PRAME protein and consisting of 125 synthetic pentadecapeptides overlapping by 11 amino acids. We successfully generated polyclonal, PRAME-specific CTL lines and elicited high-avidity CTLs, with a high proportion of cells recognizing a previously uninvestigated HLA-A*02-restricted epitope, P435-9mer (NLTHVLYPV). These PRAME-CTLs could be generated both from normal donors and from subjects with PRAME ؉ hematologic malignancies.The cytotoxic activity of our PRAMEspecific CTLs was directed not only against leukemic blasts, but also against leukemic progenitor cells as assessed by colony-forming-inhibition assays, which have been implicated in leukemia relapse. These PRAME-directed CTLs did not affect normal hematopoietic progenitors, indicating that this approach may be of value for immunotherapy of PRAME ؉ hematologic malignancies. (Blood. 2011; 117(12):3353-3362)

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Expression, epigenetic regulation, and humoral immunogenicity of cancer-testis antigens in chronic myeloid leukemia

Cited by 32 publications

References 54 publications

Cancer‐testis antigen expression and its epigenetic modulation in acute myeloid leukemia

Cancer‐testis antigen expression and its epigenetic modulation in acute myeloid leukemia

Methylation pattern of preferentially expressed antigen of melanoma in acute myeloid leukemia and myelodysplastic syndromes

High-avidity cytotoxic T lymphocytes specific for a new PRAME-derived peptide can target leukemic and leukemic-precursor cells

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