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

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 Micco () and Eugenio Montini ()
Additional contact information
Riccardo Biavasco: IRCCS San Raffaele Scientific Institute
Emanuele Lettera: IRCCS San Raffaele Scientific Institute
Kety Giannetti: IRCCS San Raffaele Scientific Institute
Diego Gilioli: IRCCS San Raffaele Scientific Institute
Stefano Beretta: IRCCS San Raffaele Scientific Institute
Anastasia Conti: IRCCS San Raffaele Scientific Institute
Serena Scala: IRCCS San Raffaele Scientific Institute
Daniela Cesana: IRCCS San Raffaele Scientific Institute
Pierangela Gallina: IRCCS San Raffaele Scientific Institute
Margherita Norelli: IRCCS San Raffaele Scientific Institute
Luca Basso-Ricci: IRCCS San Raffaele Scientific Institute
Attilio Bondanza: IRCCS San Raffaele Scientific Institute
Giulio Cavalli: Vita-Salute San Raffaele University
Maurilio Ponzoni: Vita-Salute San Raffaele University
Lorenzo Dagna: Vita-Salute San Raffaele University
Claudio Doglioni: Vita-Salute San Raffaele University
Alessandro Aiuti: IRCCS San Raffaele Scientific Institute
Ivan Merelli: Institute for Biomedical Technologies
Raffaella Micco: IRCCS San Raffaele Scientific Institute
Eugenio Montini: IRCCS San Raffaele Scientific Institute

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: 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.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24876-1

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DOI: 10.1038/s41467-021-24876-1

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