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 <i>TP53</i>, 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 <i>TP53</i> mutant compared with wild-type (WT) <i>TP53</i> AML. Moreover, in <i>TP53</i> mutant AML, STING1-dependent IFN/inflammatory signaling is increased by DNMTi treatment, whereas in AMLs with WT <i>TP53</i>, DNMTis alone have no effect. While combining DNMTis with PARPis increases IFN/inflammatory gene expression in WT <i>TP53</i> AML cells, signaling induced in <i>TP53</i> mutant AML is still several-fold higher. Notably, induction of HRD in both <i>TP53</i> 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 <i>TP53</i> status, for use of such therapies, including potential immune activation of STING1 in AML and other cancers.