1. Oncogene-induced senescence in hematopoietic progenitors features myeloid restricted hematopoiesis, chronic inflammation and histiocytosis
- Author
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Daniela Cesana, Anastasia Conti, Eugenio Montini, Stefano Beretta, Riccardo Biavasco, Claudio Doglioni, Serena Scala, Diego Gilioli, Luca Basso-Ricci, Giulio Cavalli, Pierangela Gallina, Maurilio Ponzoni, Raffaella Di Micco, Alessandro Aiuti, Ivan Merelli, Attilio Bondanza, Margherita Norelli, Kety Giannetti, Emanuele Lettera, Lorenzo Dagna, 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., Montini, E., 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
0301 basic medicine ,Myeloid ,General Physics and Astronomy ,Systemic inflammation ,Mice ,Rheumatic diseases ,0302 clinical medicine ,Principal Component Analysi ,Bone Marrow ,Hematopoiesi ,Myeloid Cells ,Myeloid Cell ,Cellular Senescence ,Principal Component Analysis ,Multidisciplinary ,Haematopoietic stem cells ,Haematopoiesis ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Histiocytoses ,medicine.symptom ,Human ,Senescence ,Proto-Oncogene Proteins B-raf ,Science ,Green Fluorescent Proteins ,Biology ,Green Fluorescent Protein ,Article ,Lentiviru ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Cell Cycle Checkpoint ,Paracrine Communication ,medicine ,Animals ,Humans ,Progenitor cell ,neoplasms ,Cyclin-Dependent Kinase Inhibitor p16 ,Inflammation ,Animal ,Tumor Necrosis Factor-alpha ,Lentivirus ,Hematopoietic Stem Cell ,General Chemistry ,Cell Cycle Checkpoints ,Oncogenes ,Histiocytosi ,Hematopoietic Stem Cells ,digestive system diseases ,Hematopoiesis ,030104 developmental biology ,Gene Expression Regulation ,Humanized mouse ,Chronic Disease ,Mutation ,Cancer research ,Bone marrow ,Histiocytosis - 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 (BRAFV600E). 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., BRAF-MAPK activating mutations are reported in histiocytoses—hematological neoplasms with widespread pro-inflammatory myeloid cells. Here, the authors show that an activating mutant BRAF in haematopoietic stem and progenitor cells causes an oncogene-induced senescence response leading to myeloid restricted haematopoiesis, inflammation and histiocytosis.
- Published
- 2021