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Oncogene-induced senescence in hematopoietic progenitors features myeloid restricted hematopoiesis, chronic inflammation and histiocytosis

2021; Nature Portfolio; Volume: 12; Issue: 1 Linguagem: Inglês

10.1038/s41467-021-24876-1

2041-1723

Riccardo Biavasco, Emanuele Lettera, Kety Giannetti, Diego Gilioli, Stefano Beretta, Anastasia Conti, Serena Scala, Daniela Cesana, Pierangela Gallina, Margherita Norelli, Luca Basso‐Ricci, Attilio Bondanza, Giulio Cavalli, Maurilio Ponzoni, Lorenzo Dagna, Claudio Doglioni, Alessandro Aiuti, Ivan Merelli, Raffaella Di Micco, Eugenio Montini,

Immune cells in cancer

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 BRAF V600E -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.