Comoli, P. | Search bioRxiv

bioRxiv2025

A 3-genes interferon signature predicts sustained complete remission in pediatric AML patients

The immunological composition of the microenvironment has shown relevance for diagnosis, prognosis, and therapy in solid tumors but remains underexplored in acute leukemias. We investigated the significance of acute myeloid leukemia (AML) bone marrow microenvironment in predicting chemosensitivity and long-term remission in pediatric patients. We analyzed 32 non-promyelocytic pediatric AML patients at diagnosis using NanoString PanCancer IO 360 assay, RNA sequencing, and deep-phenotype flow cytometry analyses. The findings were validated using the pediatric TARGET AML dataset. A short signature of three interferon (IFN)-related genes (GBP1, PARP12, TRAT1) distinguished patients with chemosensitive disease and reduced minimal residual disease after induction chemotherapy. The signature stratified patients overall, and within the clinically defined "standard-risk" group, patients with high gene expression at diagnosis had significantly longer overall survival. The leukemia microenvironment associated with this signature showed enrichment of non-exhausted CD4+ and CD8+ T cytotoxic lymphocytes and expansion of CD8+ T effector memory cells re-expressing CD45RA (TEMRA) in patients with a favorable prognosis. Our results show the importance of the bone marrow microenvironment in pediatric AML and provide tools for a refined stratification of "standard-risk" patients, lacking adequate risk-oriented therapies. They also offer a promising guide for tackling immune pathways and exploiting immune-targeted therapies. Statement of significanceWe identified a novel three-gene IFN-related signature that distinguished pediatric AML patients by chemosensitivity and remission outcomes. It stratified patients across all risk groups, including the "standard-risk" group, with high expression linked to a T-cell-enriched microenvironment and longer survival. This signature may enhance risk stratification and guide targeted immunotherapy.

cancer biology↗

bioRxiv2021

Neutrophil extracellular traps arm DC vaccination against NPM-mutant myeloproliferation

Neutrophil extracellular traps (NET) are web-like chromatin structures composed by dsDNA and histones, decorated with anti-microbial proteins. Their interaction with dendritic cells (DC) allows DC activation and maturation toward presentation of NET-associated antigens. Differently from other types of cell death that imply protein denaturation, NETosis preserves the proteins localized onto the DNA threads for proper enzymatic activity and conformational status, including immunogenic epitopes. Besides neutrophils, leukemic cells can release extracellular traps displaying leukemia-associated antigens, prototypically mutant nucleophosmin (NPMc+) that upon mutation translocates from nucleolus to the cytoplasm localizing onto NET threads. We tested NPMc+ immunogenicity through a NET/DC vaccine to treat NPMc-driven myeloproliferation in transgenic and transplantable models. Vaccination with DC loaded with NPMc+ NET (NPMc+ NET/DC) reduced myeloproliferation in transgenic mice, favoring the development of antibodies to mutant NPMc and and the induction of a CD8+ T cell response. The efficacy of this vaccine was also tested in mixed NPMc/WT bone marrow chimeras in a competitive bone marrow transplantation setting, where the NPMc+ NET/DC vaccination impaired the expansion of NPMc+ in favor of WT myeloid compartment. NPMc+ NET/DC vaccination also achieved control of an aggressive leukemia transduced with mutant NPMc, effectively inducing an anti-leukemia CD8 T cell memory response. eTOC SummaryNPMc is an AML-triggering mutation inducing translocation of NPM into the cytoplasm, allowing its association to NET threads. On NET, NPMc becomes immunogenic acting as an alarmin and exposing immunogenic peptides. We demonstrate that NET can be exploited as anti-tumor weapons in DC-based vaccination strategies.

immunology↗