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Therapy Induced Senescence Promotes Immunogenicity in Acute Myeloid Leukemia through Reduced EZH2 Activity (Cut&Tag Taz)

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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE336442 | GEO | 2026/07/24

REPOSITORIES: GEO

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Therapy Induced Senescence Promotes Immunogenicity in Acute Myeloid Leukemia through Reduced EZH2 Activity

Project description: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. This SuperSeries is composed of the SubSeries listed below.

2026-07-22 | GSE324154 | GEO

Therapy Induced Senescence Promotes Immunogenicity in Acute Myeloid Leukemia through Reduced EZH2 Activity (RNA-seq TAZ)

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AML senescence capacity is a unifying outcome predictor and plastic APL classifier

Project description:BACKGROUND Acute myeloid leukemia (AML) is a highly heterogeneous disease. The predictive role of therapy-induced senescence (TIS) in cancer treatment in general and newly diagnosed (nd) AML patients in particular is undetermined. METHODS We established a flow cytometry-based senescence assay to detectsenescence in primary patient blasts to ex vivo chemotherapy (daunorubicin or cytarabine) in patients with newly diagnosed (nd) non-M3 AML. Bulk and single-cell analyses assessed gene expression and recurrent AML mutations. TIS-related gene signatures were interrogated in additional AML patient cohorts. Computational analyses, chromatin immunoprecipitation sequencing and other functional assays characterized TIS-related leukemia biology. RESULTS Ex vivo-determined TIS capacity predicted superior disease-free and overall survival in three independent cohorts comprising 92 patients with nd non-M3 AML across diverse (cyto-)genetic subgroups. Subsequent treatment with Bcl2 inhibitors venetoclax or navitoclax demonstrated their senescence-preferential killing. By interrogating 977 nd all-subtype AML patients from three additional independent cohorts, a TIS-derived gene classifier unexpectedly identified M3-AML/acute promyelocytic leukemia cases with very high accuracy in a PML-RARA-agnostic fashion. We found the polycomb-repressive complex 2 component Suz12 to regulate this classifier. Non-M3-AML cell lines in TIS differentiated upon all-trans retinoic acid (ATRA), or died in response to the Suz12-targeting histone deacetylase (HDAC) inhibitor panobinostat. CONCLUSIONS TIS predicts superior long-term outcome in nd AML and confers unifying plasticity across molecularly highly diverse AML subtypes towards an M3-like state, which enables consolidative senolysis by Bcl2 family or HDAC inhibition, or senodifferentiation by ATRA as novel plasticity-based treatment concepts.

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Expression data from senescence-inducible Suv39h1-ERT2 primary mouse Emu-myc B-cell lymphoma

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