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. 2019 Jul 10;14(7):e0219547.
doi: 10.1371/journal.pone.0219547. eCollection 2019.

Acute myeloid leukemia immunopeptidome reveals HLA presentation of mutated nucleophosmin

Rupa Narayan  1 , Niclas Olsson  2 , Lisa E Wagar  3 , Bruno C Medeiros  1 , Everett Meyer  4 , Debra Czerwinski  5 , Michael S Khodadoust  5 , Lichao Zhang  2 , Liora Schultz  6 , Mark M Davis  3   7 , Joshua E Elias  2 , Ron Levy  5
Affiliations

Acute myeloid leukemia immunopeptidome reveals HLA presentation of mutated nucleophosmin

Rupa Narayan et al. PLoS One. .

Abstract

Somatic mutations in cancer are a potential source of cancer specific neoantigens. Acute myeloid leukemia (AML) has common recurrent mutations shared between patients in addition to private mutations specific to individuals. We hypothesized that neoantigens derived from recurrent shared mutations would be attractive targets for future immunotherapeutic approaches. Here we sought to study the HLA Class I and II immunopeptidome of thirteen primary AML tumor samples and two AML cell lines (OCI-AML3 and MV4-11) using mass spectrometry to evaluate for endogenous mutation-bearing HLA ligands from common shared AML mutations. We identified two endogenous, mutation-bearing HLA Class I ligands from nucleophosmin (NPM1). The ligands, AVEEVSLRK from two patient samples and C(cys)LAVEEVSL from OCI-AML3, are predicted to bind the common HLA haplotypes, HLA-A*03:01 and HLA-A*02:01 respectively. Since NPM1 is mutated in approximately one-third of patients with AML, the finding of endogenous HLA ligands from mutated NPM1 supports future studies evaluating immunotherapeutic approaches against this shared target, for this subset of patients with AML.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. The number of peptides from common recurrent mutations that are predicted HLA Class I binders using NPM1 as example.
From the potential 9-11mer peptides overlapping NPM1 mutation A/D/G/H, which contain a shared C terminal sequence, we evaluated the number of predicted HLA Class I binders, using available HLA-A, B, and C alleles in NetMHC3.4. Results were compared to the number of predicted HLA Class I binders from putative peptides from the corresponding wildtype NPM1 sequence. C-terminal peptide sequences from wildtype and mutant NPM1 are listed for reference (per nomenclature used by Falini et al[15] and Suzuki et al[28]).
Fig 2
Fig 2. Number and length distribution of eluted peptides.
(A) Cytogenetic and molecular features present in the thirteen patient samples are shaded dark gray on left side of panel. Right side of panel shows the number of distinct peptides eluted per sample from HLA Class I and Class II complexes. (B and C) Peptide length distribution from the combined peptide datasets of patient samples (B) and tumor cell lines (C). (D) HLA Class I and II expression by flow cytometry of patient samples (left) and cell lines (right).
Fig 3
Fig 3. Comparison of peptide similarity between patient samples.
Heatmaps based on Sorensen similarity coefficient comparing degree of similarity between peptides eluted from HLA Class I (A) and Class II (B) from patient samples. Clustering based on hierarchical cluster analysis. (C) Number of shared HLA Class I (above) and Class II DR (below) serotypes between patient samples.
Fig 4
Fig 4. Number of peptides from source proteins of leukemia associated antigens.
The number of distinct Class I and Class II peptides from (A) patient samples and (B) cell lines per source proteins of previously reported leukemia associated antigens.
Fig 5
Fig 5. Endogenous mutated peptides from NPM1 identified by MS.
(A) List of endogenous mutated Class I peptides that were identified by MS. The most likely predicted HLA binder was selected based on %rank by NetMHCpan4.0 based on the HLA haplotype for each sample. (B and C) Depiction of the protein location of eluted mutation bearing and non-mutation bearing peptides, in relation to recurrent AML hotspot mutations in proteins of interest, from patient samples (B) and cell lines (C).
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