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U.S.A."],"published-print":{"date-parts":[[2022,7,5]]},"abstract":"<jats:p>\n                    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\n                    <jats:italic>TP53<\/jats:italic>\n                    , 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\n                    <jats:italic>TP53<\/jats:italic>\n                    mutant compared with wild-type (WT)\n                    <jats:italic>TP53<\/jats:italic>\n                    AML. Moreover, in\n                    <jats:italic>TP53<\/jats:italic>\n                    mutant AML, STING1-dependent IFN\/inflammatory signaling is increased by DNMTi treatment, whereas in AMLs with WT\n                    <jats:italic>TP53<\/jats:italic>\n                    , DNMTis alone have no effect. While combining DNMTis with PARPis increases IFN\/inflammatory gene expression in WT\n                    <jats:italic>TP53<\/jats:italic>\n                    AML cells, signaling induced in\n                    <jats:italic>TP53<\/jats:italic>\n                    mutant AML is still several-fold higher. Notably, induction of HRD in both\n                    <jats:italic>TP53<\/jats:italic>\n                    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\n                    <jats:italic>TP53<\/jats:italic>\n                    status, for use of such therapies, including potential immune activation of STING1 in AML and other cancers.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2123227119","type":"journal-article","created":{"date-parts":[[2022,6,27]],"date-time":"2022-06-27T15:09:27Z","timestamp":1656342567000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":23,"title":["Activating STING1-dependent immune signaling in\n                    <i>TP53<\/i>\n                    mutant and wild-type acute myeloid leukemia"],"prefix":"10.1073","volume":"119","author":[{"given":"Aksinija A.","family":"Kogan","sequence":"first","affiliation":[{"name":"Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201"},{"name":"Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD 21201"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Topper","sequence":"additional","affiliation":[{"name":"Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna J.","family":"Dellomo","sequence":"additional","affiliation":[{"name":"Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201"},{"name":"Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD 21201"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lora","family":"Stojanovic","sequence":"additional","affiliation":[{"name":"Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201"},{"name":"Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD 21201"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lena J.","family":"McLaughlin","sequence":"additional","affiliation":[{"name":"Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201"},{"name":"Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD 21201"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T. 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