Therapy induced senescence promotes immunogenicity in acute myeloid Leukemia through reduced EZH2 activity

Abstract Chemotherapy resistance and disease relapse are major determinants of treatment failure in acute myeloid leukemia (AML). Therapy-induced senescence (TIS) is one outcome of chemotherapy, but its immunological consequences in AML remain unclear. Here we show that ex vivo chemotherapy induces senescence in a subset of therapy-naïve AML samples. TIS is marked by elevated interferon signaling, upregulation of human leukocyte antigen (HLA) class I and II molecules, and increased presentation of leukemia- and senescence-associated peptides, conferring AML cells antigen-presenting cell-like features. These changes enhance autologous CD4 + and CD8 + T cell responses against AML, both ex vivo and in patient-derived xenograft models. TIS also restores AML sensitivity to immune checkpoint blockade therapy. Mechanistically, we identify reduced Polycomb Repressive Complex 2 (PRC2) activity as central to TIS induction and its immunogenicity. PRC2 inhibition reactivates senescence-related genes and HLA expression in non-senescent AML cells, enabling T cell activation. These findings uncover a senescence-driven immune mechanism with potential to improve therapy outcomes in AML.

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Journal
Nature Communications
Published
2026-09-04
DOI
https://doi.org/10.1038/s41467-026-76853-1
Primary Topic
Telomeres, Telomerase, and Senescence
Type
article
Field-Weighted Citation Impact
0.00

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article

Therapy induced senescence promotes immunogenicity in acute myeloid Leukemia through reduced EZH2 activity

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Nature Communications
Telomeres, Telomerase, and Senescence
article

Therapy induced senescence promotes immunogenicity in acute myeloid Leukemia through reduced EZH2 activity

Edoardo Carsana, Angela Andrisani, Matteo Giovanni Carrabba, Chiara Brombin, Raffaella Di Micco, Teresa Tavella, Fabio Ciceri, Ivan Merelli, Kety Giannetti, Federico Aletti, Vincenzo Cerullo, Tatiana Volpari, Yvonne Giannoula, Luca Vago, Silvia Gregori, Salvatore Russo, Clemens A. Schmitt, Tiina Sikanen, Matteo Barcella, Simona Fusco, Janne Lehtiö, Anastasia Conti, Sara Feola, Tiziana Bonaldi, Antonella Santoro, Roberta Noberini, Martin Schönlein, Nicolò Gualandi, Chiara Bonini, Lucrezia della Volpe, Stefano Beretta, Markus Haapala, Diego Gilioli, Laura Passerini, Giacomo Farina, Rui M.M. Branca, Alessia Zangari
article en

Abstract

Abstract Chemotherapy resistance and disease relapse are major determinants of treatment failure in acute myeloid leukemia (AML). Therapy-induced senescence (TIS) is one outcome of chemotherapy, but its immunological consequences in AML remain unclear. Here we show that ex vivo chemotherapy induces senescence in a subset of therapy-naïve AML samples. TIS is marked by elevated interferon signaling, upregulation of human leukocyte antigen (HLA) class I and II molecules, and increased presentation of leukemia- and senescence-associated peptides, conferring AML cells antigen-presenting cell-like features. These changes enhance autologous CD4 + and CD8 + T cell responses against AML, both ex vivo and in patient-derived xenograft models. TIS also restores AML sensitivity to immune checkpoint blockade therapy. Mechanistically, we identify reduced Polycomb Repressive Complex 2 (PRC2) activity as central to TIS induction and its immunogenicity. PRC2 inhibition reactivates senescence-related genes and HLA expression in non-senescent AML cells, enabling T cell activation. These findings uncover a senescence-driven immune mechanism with potential to improve therapy outcomes in AML.

Nature CommunicationsVol. 17(1)
Johannes Kepler University of Linz (AT), University of Helsinki (FI), Vita-Salute San Raffaele University (IT), University of Milan (IT), Research Institute of Molecular Pathology (AT), Max Delbrück Center (DE), Science for Life Laboratory (SE), Istituto Universitario di Studi Superiori di Pavia (IT), Karolinska Institutet (SE), Federico II University Hospital (IT), Kepler Universitätsklinikum (AT), The San Raffaele Telethon Institute for Gene Therapy (IT), Istituti di Ricovero e Cura a Carattere Scientifico (IT), Institute of Biomedical Technologies (IT), National Research Council (IT), Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele (IT), European Institute of Oncology (IT), University of Naples Federico II (IT), Charité - Universitätsmedizin Berlin (DE)
Leukemia Research Foundation, Helsingin Yliopisto, European Hematology Association, Università degli Studi di Milano, Kepler Universitätsklinikum, European Commission, Fondazione Telethon, Ministero della Salute, Karolinska Institutet, Associazione Italiana per la Ricerca sul Cancro, Science for Life Laboratory, National Outstanding Youth Science Fund Project of National Natural Science Foundation of China, Helsinki Institute of Life Science, Helsingin Yliopisto
Good health and well-being
Openalex Percentile: Top 11%
Telomeres, Telomerase, and Senescence
DOIOpen Access PDFOpenAlex
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