Upregulation of interferon signaling predicts sustained complete remission in pediatric AML patients

Abstract The immunological composition of the microenvironment has shown relevance for diagnosis, prognosis, and therapy in solid tumors, while it remains underexplored in acute leukemias. In this study, we investigated the significance of the acute myeloid leukemia (AML) bone marrow microenvironment in predicting chemosensitivity and long-term remission outcomes in pediatric patients. To this aim, we analyzed 32 non-promyelocytic pediatric AML patients at diagnosis using the NanoString PanCancer IO 360 assay and RNA-Sequencing and we validated our findings in the online available TARGET AML pediatric dataset. A short signature of 3 Interferon (IFN)-related genes (GBP1, PARP12, TRAT1) significantly distinguished chemosensitive diseases and stratified patients assigned to standard risk group, as per current treatment protocols, into 2 groups: patients with a high enrichment of the 3 genes at diagnosis had a significantly longer overall survival compared with patients with a low enrichment. The leukemia microenvironment associated with this signature showed a contextual enhancement of TH1/cytotoxic/NK-related pathways. Our results demonstrate the importance of immune response in the tumor microenvironment of pediatric AML and provide tools for a more refined stratification of pediatric patients otherwise categorized as “standard-risk” and as such, lacking adequate risk-oriented therapeutic strategies. Moreover, they offer a promising guide to tackle immune pathways and potentially exploit immune-targeted therapies.