1. Oncogene-induced senescence in hematopoietic progenitors features myeloid restricted hematopoiesis, chronic inflammation and histiocytosis.
- Author
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Biavasco R, Lettera E, Giannetti K, Gilioli D, Beretta S, Conti A, Scala S, Cesana D, Gallina P, Norelli M, Basso-Ricci L, Bondanza A, Cavalli G, Ponzoni M, Dagna L, Doglioni C, Aiuti A, Merelli I, Di Micco R, and Montini E
- Subjects
- Animals, Bone Marrow pathology, Cell Cycle Checkpoints genetics, Chronic Disease, Cyclin-Dependent Kinase Inhibitor p16 metabolism, Gene Expression Regulation, Green Fluorescent Proteins metabolism, Histiocytosis complications, Humans, Inflammation complications, Lentivirus genetics, Mice, Mutation genetics, Paracrine Communication, Principal Component Analysis, Proto-Oncogene Proteins B-raf genetics, Tumor Necrosis Factor-alpha antagonists & inhibitors, Tumor Necrosis Factor-alpha metabolism, Cellular Senescence genetics, Hematopoiesis genetics, Hematopoietic Stem Cells metabolism, Histiocytosis pathology, Inflammation pathology, Myeloid Cells pathology, Oncogenes
- Abstract
Activating mutations in the BRAF-MAPK pathway have been reported in histiocytoses, hematological inflammatory neoplasms characterized by multi-organ dissemination of pro-inflammatory myeloid cells. Here, we generate a humanized mouse model of transplantation of human hematopoietic stem and progenitor cells (HSPCs) expressing the activated form of BRAF (BRAF
V600E ). All mice transplanted with BRAFV600E -expressing HSPCs succumb to bone marrow failure, displaying myeloid-restricted hematopoiesis and multi-organ dissemination of aberrant mononuclear phagocytes. At the basis of this aggressive phenotype, we uncover the engagement of a senescence program, characterized by DNA damage response activation and a senescence-associated secretory phenotype, which affects also non-mutated bystander cells. Mechanistically, we identify TNFα as a key determinant of paracrine senescence and myeloid-restricted hematopoiesis and show that its inhibition dampens inflammation, delays disease onset and rescues hematopoietic defects in bystander cells. Our work establishes that senescence in the human hematopoietic system links oncogene-activation to the systemic inflammation observed in histiocytic neoplasms., (© 2021. The Author(s).)- Published
- 2021
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