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Oncogene-induced maladaptive activation of trained immunity in the pathogenesis and treatment of Erdheim-Chester disease.
- Source :
-
Blood [Blood] 2021 Oct 28; Vol. 138 (17), pp. 1554-1569. - Publication Year :
- 2021
-
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.<br /> (© 2021 by The American Society of Hematology.)
- Subjects :
- Cells, Cultured
Epigenesis, Genetic
Erdheim-Chester Disease immunology
Erdheim-Chester Disease pathology
Humans
Immunity
Inflammation immunology
Inflammation pathology
Macrophages immunology
Macrophages metabolism
Macrophages pathology
Oncogenes
Point Mutation
Proto-Oncogene Proteins B-raf immunology
Erdheim-Chester Disease genetics
Inflammation genetics
Proto-Oncogene Proteins B-raf genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1528-0020
- Volume :
- 138
- Issue :
- 17
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 34077954
- Full Text :
- https://doi.org/10.1182/blood.2020009594