Activating STING1-dependent immune signaling in TP53 mutant and wild-type acute myeloid leukemia

• Published in: Proceedings of the National Academy of Sciences - PNAS 2022-07, Vol.119 (27), p.e2123227119
• Main Authors: Kogan, Aksinija A, Topper, Michael J, Dellomo, Anna J, Stojanovic, Lora, McLaughlin, Lena J, Creed, T Michael, Eberly, Christian L, Kingsbury, Tami J, Baer, Maria R, Kessler, Michael D, Baylin, Stephen B, Rassool, Feyruz V
• Format: Article
• Language: English
• Subjects: Acute myeloid leukemia; Adenosine diphosphate; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biological Sciences; Cancer; DNA methyltransferase; DNA-Cytosine Methylases - antagonists & inhibitors; Endogenous retroviruses; Gene expression; Homologous recombination; Homologous Recombination - genetics; Homology; Humans; Immune response; Immunosuppressive agents; Inflammasomes; Inflammasomes - metabolism; Inflammation; Inhibitors; Interferon; Leukemia; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - immunology; Membrane Proteins - immunology; Mimicry; Mutants; Mutation; p53 Protein; Poly(ADP-ribose) Polymerase Inhibitors - pharmacology; Poly(ADP-ribose) Polymerase Inhibitors - therapeutic use; Ribose; Signal Transduction; Signaling; Solid tumors; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.2123227119

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 , 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 mutant compared with wild-type (WT) AML. Moreover, in mutant AML, STING1-dependent IFN/inflammatory signaling is increased by DNMTi treatment, whereas in AMLs with WT , DNMTis alone have no effect. While combining DNMTis with PARPis increases IFN/inflammatory gene expression in WT AML cells, signaling induced in mutant AML is still several-fold higher. Notably, induction of HRD in both 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 status, for use of such therapies, including potential immune activation of STING1 in AML and other cancers.