Activating STING1-dependent immune signaling inTP53mutant 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.

Mutant p53 gains oncogenic functions through a chromosomal instability-induced cytosolic DNA response

“…6k ). Supported by recent studies showing that the acquisition of aneuploidy drives mutp53-associated GOF phenotypes 34 , that STING activity is often increased in TP53 –mutant compared with wt TP53 tumors 77 , and that cGAS and STING are required for CIN-driven tumor progression 65 , our findings provide significant insight into not only the GOF mechanisms of TP53 mutations but also all inactivating mutations of p53 that lead to genomic instability to promote immune suppression and metastasis during tumor development and tumor progression. This suggests that a strategy for targeting tumor cell-intrinsic NC-NF-κB signaling could be an impactful approach to treating cancers with TP53 inactivation-induced CIN.…”

Human endogenous retroviruses as epigenetic therapeutic targets in TP53-mutated diffuse large B-cell lymphoma

“…Mutant TP53 shapes the immune landscape of the TME by down-regulating MHC-1/II expression and T cell infiltration, 9 decitabine treatment increased ERV expression, IFN production, and mediated viral mimicry anti-tumor immunity, which is why, TP53 mut DLBCL, resistant to R-CHOP, could be eliminated by decitabine combined with chemotherapy (DR-CHOP). Consistently, in MDS and AML, decitabine induces higher IFN production 34 and improves responses in TP53 mut patients. 35 , 36 These observations demonstrated that reprogramming TME was essentially involved in decitabine-treated TP53 mut hematological malignancies through fostering IFN production and T cell activation.…”

cGAS-STING, inflammasomes and pyroptosis: an overview of crosstalk mechanism of activation and regulation

“…In addition, monocytes in SLE patients showed considerable activation of caspase-1 [ 200 ]. In acute myeloid leukemia (AML) with TP53 mutations, the therapeutic agent DNA methyltransferase inhibitors (DNMTis) expressed endogenous retroviruses (ERVs), IFNs and activated NLRP3 inflammasome in a STING-dependent manner [ 201 ]. DNA polymerase β (Pol β) was significantly decreased in peripheral blood mononuclear cells (PBMCs) of RA patients and mice with collagen-induced arthritis (CIA).…”