Mutational landscape of the transcriptome offers putative targets for immunotherapy of myeloproliferative neoplasms

Fiorella Schischlik, Roland Jäger, Felix Rosebrock, Eva Hug, Michael Schuster, Raimund Holly, Elisabeth Fuchs, Jelena D. Milosevic Feenstra, Edith Bogner, Bettina Gisslinger, Martin Schalling, Elisa Rumi, Daniela Pietra, Gottfried Fischer, Ingrid Faé, Loan Vulliard, Jörg Menche, Torsten Haferlach, Manja Meggendorfer, Anna StengelChristoph Bock, Mario Cazzola, Heinz Gisslinger, Robert Kralovics

Research output: Contribution to journalArticle

Abstract

Ph-negative myeloproliferative neoplasms (MPNs) are hematological cancers that can be subdivided into entities with distinct clinical features. Somatic mutations in JAK2, CALR, and MPL have been described as drivers of the disease, together with a variable landscape of nondriver mutations. Despite detailed knowledge of disease mechanisms, targeted therapies effective enough to eliminate MPN cells are still missing. In this study of 113 MPN patients, we aimed to comprehensively characterize the mutational landscape of the granulocyte transcriptome using RNA sequencing data and subsequently examine the applicability of immunotherapeutic strategies for MPN patients. Following implementation of customized workflows and data filtering, we identified a total of 13 (12/13 novel) gene fusions, 231 nonsynonymous single nucleotide variants, and 21 insertions and deletions in 106 of 113 patients. We found a high frequency of SF3B1-mutated primary myelofibrosis patients (14%) with distinct 3' splicing patterns, many of these with a protein-altering potential. Finally, from all mutations detected, we generated a virtual peptide library and used NetMHC to predict 149 unique neoantigens in 62% of MPN patients. Peptides from CALR and MPL mutations provide a rich source of neoantigens as a result of their unique ability to bind many common MHC class I molecules. Finally, we propose that mutations derived from splicing defects present in SF3B1-mutated patients may offer an unexplored neoantigen repertoire in MPNs. We validated 35 predicted peptides to be strong MHC class I binders through direct binding of predicted peptides to MHC proteins in vitro. Our results may serve as a resource for personalized vaccine or adoptive cell-based therapy development.

Original languageEnglish
Pages (from-to)199-210
Number of pages12
JournalBlood
Volume134
Issue number2
DOIs
Publication statusPublished - Jul 11 2019

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ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Schischlik, F., Jäger, R., Rosebrock, F., Hug, E., Schuster, M., Holly, R., Fuchs, E., Milosevic Feenstra, J. D., Bogner, E., Gisslinger, B., Schalling, M., Rumi, E., Pietra, D., Fischer, G., Faé, I., Vulliard, L., Menche, J., Haferlach, T., Meggendorfer, M., ... Kralovics, R. (2019). Mutational landscape of the transcriptome offers putative targets for immunotherapy of myeloproliferative neoplasms. Blood, 134(2), 199-210. https://doi.org/10.1182/blood.2019000519