Therapy induced senescence promotes immunogenicity in acute myeloid Leukemia through reduced EZH2 activity
- Diego Gilioli
- Simona Fusco
- Teresa Tavella
- Tatiana Volpari
- Antonella Santoro
- Martin Schönlein
- Kety Giannetti
- Edoardo Carsana
- Nicolò Gualandi
- Roberta Noberini
- Chiara Brombin
- Salvatore Russo
- Sara Feola
- Yvonne Giannoula
- Rui M. M. Branca
- Janne Lehtiö
- Tiina M. Sikanen
- Markus Haapala
- Laura Passerini
- Angela Andrisani
- Giacomo Farina
- Alessia Zangari
- Anastasia Conti
- Lucrezia della Volpe
- Matteo Barcella
- Stefano Beretta
- Federico Mario Aletti
- Matteo Giovanni Carrabba
- Silvia Gregori
- Chiara Bonini
- Ivan Merelli
- Fabio Ciceri
- Vincenzo Cerullo
- Tiziana Bonaldi
- Luca Vago
- Clemens A. Schmitt
- Raffaella Di Micco
2026-09-04
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.