biostudies-literatureBelenki DBundesministerium für Bildung und Forschung (Federal Ministry of Education and Research)Bundesministerium für Bildung und ForschungDeutsche ForschungsgemeinschaftDeutsche Forschungsgemeinschaft (German Research Foundation)Bundesministerium für GesundheitDeutsche KrebshilfeBundesministerium für Gesundheit (Federal Ministry of Health, Germany)Deutsche Krebshilfe (German Cancer Aid)3079https://www.ebi.ac.uk/biostudies/studies/S-EPMC11955568biostudies-literatureUnknown16(1)Cellular senescence is a stress-inducible state switch relevant in aging, tumorigenesis and cancer therapy. Beyond a lasting arrest, senescent cells are characterized by profound chromatin remodeling and transcriptional reprogramming. We show here myeloid-skewed aberrant lineage plasticity and its immunological ramifications in therapy-induced senescence (TIS) of primary human and murine B-cell lymphoma. We find myeloid transcription factor (TF) networks, specifically AP-1-, C/EBPβ- and PU.1-governed transcriptional programs, enriched in TIS but not in equally chemotherapy-exposed senescence-incapable cancer cells. Dependent on these master TF, TIS lymphoma cells adopt a lineage-promiscuous state with properties of monocytic-dendritic cell (DC) differentiation. TIS lymphoma cells are prefeNature communicationsSenescence-associated lineage-aberrant plasticity evokes T-cell-mediated tumor control.PMC11955568e:Med program project SeneSys: 031L0189AEuropean Union ERA PerMed, HiRisk-HiGainGO 2688/1 1SCHM 1633/9-27011377629SCHM 1633/11-1Lee SKandler GScharnagl EReimann MDorr JRBrzezicha BShao ZPardon KSchonlein MWolf JBischof OYu YBelenki DNabuco Leva Ferreira de Freitas JAHick TPChapuy BSchmitt CAMilanovic MLeser UScheidereit CBhattacharya AFan DNYBittner AKase JDu JRichter-Pechanska PLau ACai XThiessen NfalseSenescence-associated lineage-aberrant plasticity evokes T-cell-mediated tumor control.Cellular senescence is a stress-inducible state switch relevant in aging, tumorigenesis and cancer therapy. Beyond a lasting arrest, senescent cells are characterized by profound chromatin remodeling and transcriptional reprogramming. We show here myeloid-skewed aberrant lineage plasticity and its immunological ramifications in therapy-induced senescence (TIS) of primary human and murine B-cell lymphoma. We find myeloid transcription factor (TF) networks, specifically AP-1-, C/EBPβ- and PU.1-governed transcriptional programs, enriched in TIS but not in equally chemotherapy-exposed senescence-incapable cancer cells. Dependent on these master TF, TIS lymphoma cells adopt a lineage-promiscuous state with properties of monocytic-dendritic cell (DC) differentiation. TIS lymphoma cells are prefe2025-01-01T00:00:00Z2025 Mar2026-06-01T07:44:10.44Z2026-04-08T10:29:46.775ZS-EPMC119555684015949710.1038/s41467-025-57429-x