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NPM1 and DNMT3A mutations are associated with distinct blast immunophenotype in acute myeloid leukemia

The immune system is important for elimination of residual leukemic cells during acute myeloid leukemia (AML) therapy. Anti-leukemia immune response can be inhibited by various mechanisms leading to immune evasion and disease relapse. Selected markers of immune escape were analyzed on AML cells from...

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Autores principales: Kuželová, Kateřina, Brodská, Barbora, Marková, Jana, Petráčková, Martina, Schetelig, Johannes, Ransdorfová, Šárka, Gašová, Zdenka, Šálek, Cyril
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2022
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9090295/
https://www.ncbi.nlm.nih.gov/pubmed/35558161
http://dx.doi.org/10.1080/2162402X.2022.2073050
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author Kuželová, Kateřina
Brodská, Barbora
Marková, Jana
Petráčková, Martina
Schetelig, Johannes
Ransdorfová, Šárka
Gašová, Zdenka
Šálek, Cyril
author_facet Kuželová, Kateřina
Brodská, Barbora
Marková, Jana
Petráčková, Martina
Schetelig, Johannes
Ransdorfová, Šárka
Gašová, Zdenka
Šálek, Cyril
author_sort Kuželová, Kateřina
collection PubMed
description The immune system is important for elimination of residual leukemic cells during acute myeloid leukemia (AML) therapy. Anti-leukemia immune response can be inhibited by various mechanisms leading to immune evasion and disease relapse. Selected markers of immune escape were analyzed on AML cells from leukapheresis at diagnosis (N = 53). Hierarchical clustering of AML immunophenotypes yielded distinct genetic clusters. In the absence of DNMT3A mutation, NPM1 mutation was associated with decreased HLA expression and low levels of other markers (CLIP, PD-L1, TIM-3). Analysis of an independent cohort confirmed decreased levels of HLA transcripts in patients with NPM1 mutation. Samples with combined NPM1 and DNMT3A mutations had high CLIP surface amount suggesting reduced antigen presentation. TIM-3 transcript correlated not only with TIM-3 surface protein but also with CLIP and PD-L1. In our cohort, high levels of TIM-3/PD-L1/CLIP were associated with lower survival. Our results suggest that AML genotype is related to blast immunophenotype, and that high TIM-3 transcript levels in AML blasts could be a marker of immune escape. Cellular pathways regulating resistance to the immune system might contribute to the predicted response to standard therapy of patients in specific AML subgroups and should be targeted to improve AML treatment.
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spelling pubmed-90902952022-05-11 NPM1 and DNMT3A mutations are associated with distinct blast immunophenotype in acute myeloid leukemia Kuželová, Kateřina Brodská, Barbora Marková, Jana Petráčková, Martina Schetelig, Johannes Ransdorfová, Šárka Gašová, Zdenka Šálek, Cyril Oncoimmunology Original Research The immune system is important for elimination of residual leukemic cells during acute myeloid leukemia (AML) therapy. Anti-leukemia immune response can be inhibited by various mechanisms leading to immune evasion and disease relapse. Selected markers of immune escape were analyzed on AML cells from leukapheresis at diagnosis (N = 53). Hierarchical clustering of AML immunophenotypes yielded distinct genetic clusters. In the absence of DNMT3A mutation, NPM1 mutation was associated with decreased HLA expression and low levels of other markers (CLIP, PD-L1, TIM-3). Analysis of an independent cohort confirmed decreased levels of HLA transcripts in patients with NPM1 mutation. Samples with combined NPM1 and DNMT3A mutations had high CLIP surface amount suggesting reduced antigen presentation. TIM-3 transcript correlated not only with TIM-3 surface protein but also with CLIP and PD-L1. In our cohort, high levels of TIM-3/PD-L1/CLIP were associated with lower survival. Our results suggest that AML genotype is related to blast immunophenotype, and that high TIM-3 transcript levels in AML blasts could be a marker of immune escape. Cellular pathways regulating resistance to the immune system might contribute to the predicted response to standard therapy of patients in specific AML subgroups and should be targeted to improve AML treatment. Taylor & Francis 2022-05-06 /pmc/articles/PMC9090295/ /pubmed/35558161 http://dx.doi.org/10.1080/2162402X.2022.2073050 Text en © 2022 The Author(s). Published with license by Taylor & Francis Group, LLC. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) ), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Research
Kuželová, Kateřina
Brodská, Barbora
Marková, Jana
Petráčková, Martina
Schetelig, Johannes
Ransdorfová, Šárka
Gašová, Zdenka
Šálek, Cyril
NPM1 and DNMT3A mutations are associated with distinct blast immunophenotype in acute myeloid leukemia
title NPM1 and DNMT3A mutations are associated with distinct blast immunophenotype in acute myeloid leukemia
title_full NPM1 and DNMT3A mutations are associated with distinct blast immunophenotype in acute myeloid leukemia
title_fullStr NPM1 and DNMT3A mutations are associated with distinct blast immunophenotype in acute myeloid leukemia
title_full_unstemmed NPM1 and DNMT3A mutations are associated with distinct blast immunophenotype in acute myeloid leukemia
title_short NPM1 and DNMT3A mutations are associated with distinct blast immunophenotype in acute myeloid leukemia
title_sort npm1 and dnmt3a mutations are associated with distinct blast immunophenotype in acute myeloid leukemia
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9090295/
https://www.ncbi.nlm.nih.gov/pubmed/35558161
http://dx.doi.org/10.1080/2162402X.2022.2073050
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