Transcriptomics

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


ABSTRACT: In the present study we show that in the subset of acute myeloid leukemias (AML) 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 STING1 dependent manner. We previously reported in solid tumors that PARPis combined with DNMTis 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 WT TP53 AML. Moreover, in TP53 mutant AML, STING1-dependent IFN/inflammatory signaling is increased by DNMTi treatment, whereas in AMLs with wild-type (WT) TP53, DNMTis alone have no effect. However, while combining DNMTis with PARPIs now 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 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, and a personalized approach, stratifying by p53 status, for use of such therapies, including potential immune activation of STING1 in AML and other cancers.

ORGANISM(S): Homo sapiens

PROVIDER: GSE197405 | GEO | 2022/03/07

REPOSITORIES: GEO

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