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Mutated nucleophosmin 1 as immunotherapy target in acute myeloid leukemia
- Source :
- Journal of Clinical Investigation. February, 2019, Vol. 129 Issue 2, p774, 12 p.
- Publication Year :
- 2019
-
Abstract
- The most frequent subtype of acute myeloid leukemia (AML) is defined by mutations in the nucleophosmin 1 (NPM1) gene. Mutated NPM1 ([DELTA]NPM1) is an attractive target for immunotherapy, since it is an essential driver gene and 4 bp frameshift insertions occur in the same hotspot in 30%-35% of AMLs, resulting in a C-terminal alternative reading frame of 11 aa. By searching the HLA class I ligandome of primary AMLs, we identified multiple [DELTA]NPM1-derived peptides. For one of these peptides, HLA-A*02:01-binding CLAVEEVSL, we searched for specific T cells in healthy individuals using peptide-HLA tetramers. Tetramer-positive [CD8.sup.+] T cells were isolated and analyzed for reactivity against primary AMLs. From one clone with superior antitumor reactivity, we isolated the T cell receptor (TCR) and demonstrated specific recognition and lysis of HLA-A*02:01-positive [DELTA]NPM1 AML after retroviral transfer to [CD8.sup.+] and [CD4.sup.+] T cells. Antitumor efficacy of TCR-transduced T cells was confirmed in immunodeficient mice engrafted with a human AML cell line expressing [DELTA]NPM1. In conclusion, the data show that [DELTA]NPM1-derived peptides are presented on AML and that CLAVEEVSL is a neoantigen that can be efficiently targeted on AML by [DELTA]NPM1 TCR gene transfer. Immunotherapy targeting [DELTA]NPM1 may therefore contribute to treatment of AML.<br />Introduction Acute myeloid leukemia (AML) is characterized by accumulation of malignant myeloid precursor cells that are arrested in differentiation in the bone marrow. Standard therapy of AML consists of induction [...]
Details
- Language :
- English
- ISSN :
- 00219738
- Volume :
- 129
- Issue :
- 2
- Database :
- Gale General OneFile
- Journal :
- Journal of Clinical Investigation
- Publication Type :
- Academic Journal
- Accession number :
- edsgcl.574176422
- Full Text :
- https://doi.org/10.1172/JCI97482