{"doi":"10.1073/pnas.2123227119","title":"Activating STING1-dependent immune signaling in <i>TP53</i> mutant and wild-type acute myeloid leukemia","abstract":"DNA methyltransferase inhibitors (DNMTis) reexpress hypermethylated genes in cancers and leukemias and also activate endogenous retroviruses (ERVs), leading to interferon (IFN) signaling, in a process known as viral mimicry. In the present study we show that in the subset of acute myeloid leukemias (AMLs) with mutations in TP53 , associated with poor prognosis, DNMTis, important drugs for treatment of AML, enable expression of ERVs and IFN and inflammasome signaling in a STING-dependent manner. We previously reported that in solid tumors poly ADP ribose polymerase inhibitors (PARPis) combined with DNMTis to induce an IFN/inflammasome response that is dependent on STING1 and is mechanistically linked to generation of a homologous recombination defect (HRD). We now show that STING1 activity is actually increased in TP53 mutant compared with wild-type (WT) TP53 AML. Moreover, in TP53 mutant AML, STING1-dependent IFN/inflammatory signaling is increased by DNMTi treatment, whereas in AMLs with WT TP53 , DNMTis alone have no effect. While combining DNMTis with PARPis increases IFN/inflammatory gene expression in WT TP53 AML cells, signaling induced in TP53 mutant AML is still several-fold higher. Notably, induction of HRD in both TP53 mutant and WT AMLs follows the pattern of STING1-dependent IFN and inflammatory signaling that we have observed with drug treatments. These findings increase our understanding of the mechanisms that underlie DNMTi + PARPi treatment, and also DNMTi combinations with immune therapies, suggesting a personalized approach that statifies by TP53 status, for use of such therapies, including potential immune activation of STING1 in AML and other cancers.","journal":"Proceedings of the National Academy of Sciences","year":2022,"id":253554,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":22,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9513,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":644952,"name":"Michael J. Topper","orcid":"0000-0002-2778-4920","position":1,"is_corresponding":false},{"id":770689,"name":"Anna J. Dellomo","orcid":"0000-0003-0310-8474","position":2,"is_corresponding":false},{"id":899501,"name":"Lora Stojanovic","orcid":"0000-0003-1347-6334","position":3,"is_corresponding":false},{"id":899502,"name":"Lena J. McLaughlin","orcid":"0000-0002-5831-0381","position":4,"is_corresponding":false},{"id":900143,"name":"T. Michael Creed","orcid":null,"position":5,"is_corresponding":false},{"id":771230,"name":"Christian Eberly","orcid":null,"position":6,"is_corresponding":false},{"id":407502,"name":"Tami J. Kingsbury","orcid":"0000-0003-3095-3788","position":7,"is_corresponding":false},{"id":474925,"name":"Maria R. Baer","orcid":"0000-0002-9499-1348","position":8,"is_corresponding":false},{"id":24981,"name":"Michael D. Kessler","orcid":"0000-0003-1258-5221","position":9,"is_corresponding":false},{"id":1841,"name":"Stephen B. Baylin","orcid":"0000-0003-3697-3798","position":10,"is_corresponding":false},{"id":770691,"name":"Feyruz V. Rassool","orcid":"0000-0001-6252-7439","position":11,"is_corresponding":false},{"id":861228,"name":"Aksinija A. Kogan","orcid":null,"position":0,"is_corresponding":true}],"reference_count":82,"raw_metadata":null,"created_at":"2026-07-19T00:24:59.596040Z","pmid":"35759659","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}