Mutated nucleophosmin 1 as immunotherapy target in acute myeloid leukemia
Dyantha I. van der Lee, … , J.H. Frederik Falkenburg, Marieke Griffioen
Dyantha I. van der Lee, … , J.H. Frederik Falkenburg, Marieke Griffioen
Published February 1, 2019; First published January 14, 2019
Citation Information: J Clin Invest. 2019;129(2):774-785. https://doi.org/10.1172/JCI97482.
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Categories: Research Article Hematology

Mutated nucleophosmin 1 as immunotherapy target in acute myeloid leukemia

Abstract

The most frequent subtype of acute myeloid leukemia (AML) is defined by mutations in the nucleophosmin 1 (NPM1) gene. Mutated NPM1 (ΔNPM1) 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 ΔNPM1-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+ 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 ΔNPM1 AML after retroviral transfer to CD8+ and CD4+ T cells. Antitumor efficacy of TCR-transduced T cells was confirmed in immunodeficient mice engrafted with a human AML cell line expressing ΔNPM1. In conclusion, the data show that ΔNPM1-derived peptides are presented on AML and that CLAVEEVSL is a neoantigen that can be efficiently targeted on AML by ΔNPM1 TCR gene transfer. Immunotherapy targeting ΔNPM1 may therefore contribute to treatment of AML.

Authors

Dyantha I. van der Lee, Rogier M. Reijmers, Maria W. Honders, Renate S. Hagedoorn, Rob C.M. de Jong, Michel G.D. Kester, Dirk M. van der Steen, Arnoud H. de Ru, Christiaan Kweekel, Helena M. Bijen, Inge Jedema, Hendrik Veelken, Peter A. van Veelen, Mirjam H.M. Heemskerk, J.H. Frederik Falkenburg, Marieke Griffioen

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Figure 1

DNA and protein sequences for WTNPM1 and ΔNPM1.

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DNA and protein sequences for WTNPM1 and ΔNPM1. Nucleic and amino acid s...
Nucleic and amino acid sequences are shown for WTNPM1 (upper) and ΔNPM1 (lower). Indicated is a TCTG insertion between c.863_864 in the coding sequence of NPM1, which is the most frequent frameshift mutation in the hotspot region. Translated aa sequences are shown until the termination sequence (stop, indicated by asterisks). As a consequence of the TCTG insertion, the C-terminal aa CLAVEEVSLRK of ΔNPM1 are translated in an alternative reading frame. WT and mutant aa are indicated in gray and red, respectively.