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Cyclin-A1 expression in acute myeloid leukemia stem cells and its representation as an immunogenic antigen that can be targeted by cytotoxic T cells.
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| Zeitschriftentitel: | Journal of Clinical Oncology |
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| Personen und Körperschaften: | , , , , , , |
| In: | Journal of Clinical Oncology, 30, 2012, 15_suppl, S. 2523-2523 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
American Society of Clinical Oncology (ASCO)
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| Schlagwörter: |
| Zusammenfassung: | <jats:p> 2523 </jats:p><jats:p> Background: Targeted T-cell therapy represents a more specific and less toxic alternative to allogeneic stem cell transplantation for providing a cytotoxic anti-leukemic response to eliminate the leukemic stem cell (LSC) compartment in acute myeloid leukemia (AML). The aim of this study was to identify a leukemia-associated antigen that is both immunogenic and exhibits selective high expression in AML LSCs. Methods: Expression microarrays of leukemic and normal cells were used to identify suitable candidate genes. Cyclin-A1 appeared to be differentially expressed, and was further analyzed by quantitative RT-PCR, intracellular FACS staining, and immunofluorescence microscopy. T-cell clones specific for cyclin-A1 were generated by stimulation in vitro with an overlapping peptide library, followed by cloning of responding cells. Specificity of the clones was documented by intracellular IFNg and tetramer staining. Cytotoxicity was determined by chromium release and caspase-3 cleavage assays. Results: To identify target candidates with a suitable expression pattern, microarray data from LSCs, hematopoietic cells and healthy tissues were compared. Cyclin-A1 was found to be selectively expressed in LSCs of >50% of AML patients, but minimally expressed in normal tissues with exception of testis. Using dendritic cells and monocytes pulsed with a cyclin-A1 peptide library, T-cells were generated against eight cyclin-A1 oligopeptides. Two HLA A2-restricted epitopes were further characterized, and specific T-cell clones recognized both peptide-pulsed target cells and the HLA A2-positive AML line THP-1. Furthermore, cyclin-A1-specific CD8 T-cells lysed primary AML cells. Conclusions: Cyclin-A1, known to be important in meiosis, is expressed in AML LSCs and testis and can be targeted by T-cells. Thus, cyclin-A1 is the first prototypic LSC-associated leukemia-testis-antigen. Cyclin-A1 already has been shown to be leukemogenic in mice and to promote proliferation and survival in AML blasts. This pro-oncogenic activity, together with high expression levels and a multitude of immunogenic epitopes, make it a promising target for T-cell based therapy approaches. </jats:p> |
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| Umfang: | 2523-2523 |
| ISSN: |
0732-183X
1527-7755 |
| DOI: | 10.1200/jco.2012.30.15_suppl.2523 |