Oncogene-induced maladaptive activation of trained immunity in the pathogenesis and treatment of Erdheim-Chester disease.

Lorenzo Dagna, Giacomo De Luca, Alessandro Tomelleri, Corrado Campochiaro, Leo A B Joosten, Charles A Dinarello, Anna Kajaste-Rudnitski, Julien Haroche, Simone Cardaci, Simone Cenci, Daniela Gnani, Claudio Doglioni, Marina Ferrarini, Elisabetta Ferrero, Alessandra Boletta, Angelo D'Alessandro, Eugenio Montini, Mihai G Netea, Giulio Cavalli, Maddalena Panigada, Riccardo Biavasco, Davide Stefanoni, Travis Nemkov, Jorge Domínguez-Andrés, Rob J Arts, Ivan Merelli, Davide Mazza, Samuel Zambrano, Raffaella Molteni, Eleonora Cantoni, Isak W Tengesdal, Philippe Maksud, Francesco Piras, Daniela Cesana, Laura Cassina, Gianfranco Distefano, Alessia Loffreda

Journal: Blood 2021;138(17):1554-1569

PMID: 34077954

Free Full Text on Elsevier Science View on PubMed

Abstract

Trained immunity (TI) is a proinflammatory program induced in monocyte/macrophages upon sensing of specific pathogens and is characterized by immunometabolic and epigenetic changes that enhance cytokine production. Maladaptive activation of TI (ie, in the absence of infection) may result in detrimental inflammation and development of disease; however, the exact role and extent of inappropriate activation of TI in the pathogenesis of human diseases is undetermined. In this study, we uncovered the oncogene-induced, maladaptive induction of TI in the pathogenesis of a human inflammatory myeloid neoplasm (Erdheim-Chester disease, [ECD]), characterized by the BRAFV600E oncogenic mutation in monocyte/macrophages and excess cytokine production. Mechanistically, myeloid cells expressing BRAFV600E exhibit all molecular features of TI: activation of the AKT/mammalian target of rapamycin signaling axis; increased glycolysis, glutaminolysis, and cholesterol synthesis; epigenetic changes on promoters of genes encoding cytokines; and enhanced cytokine production leading to hyperinflammatory responses. In patients with ECD, effective therapeutic strategies combat this maladaptive TI phenotype; in addition, pharmacologic inhibition of immunometabolic changes underlying TI (ie, glycolysis) effectively dampens cytokine production by myeloid cells. This study revealed the deleterious potential of inappropriate activation of TI in the pathogenesis of human inflammatory myeloid neoplasms and the opportunity for inhibition of TI in conditions characterized by maladaptive myeloid-driven inflammation.

Address: Division of Genetics and Cell Biology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Milan, Italy.; San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS, San Raffaele Scientific Institute, Milan, Italy.; Department of Biochemistry and Molecular Genetics, University of Colorado Denver, Aurora, CO.; Vita-Salute San Raffaele University, Milan, Italy.; Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.; National Research Council, Institute for Biomedical Technologies, Segrate, Italy.; Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Milan, Italy.; Department of Medicine, University of Colorado Denver, Aurora, CO.; Assistance Publique-Hôpitaux de Paris (AP-HP), Médecine Nucléaire Groupe Hospitalier Pitié Salpêtrière, Paris, France.; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.; Unit of Immunology, Rheumatology, Allergy, and Rare Diseases, IRCCS San Raffaele Scientific Institute.; Department of Medical Genetics, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.; Service de Médecine Interne, AP-HP, Sorbonne Université.; Centre National de Référence des Histiocytoses, Hôpital Pitié-Salpêtrière, Paris, France, Paris, France.; Department of Pathology, IRCCS San Raffaele Scientific Institute, Milan, Italy.; Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy; and.; Department of Immunology and Metabolism, Life and Medical Sciences Institute, University of Bonn, Bonn, Germany.

DOI: 10.1182/blood.2020009594

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MeSH Terms: Cells, Cultured, Epigenesis, Genetic, Erdheim-Chester Disease, Humans, Immunity, Inflammation, Macrophages, Oncogenes, Point Mutation, Proto-Oncogene Proteins B-raf