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.

Biavasco, R., Lettera, E., Giannetti, K., Gilioli, D., Beretta, S., Conti, A., et al. (2021). Oncogene-induced senescence in hematopoietic progenitors features myeloid restricted hematopoiesis, chronic inflammation and histiocytosis. NATURE COMMUNICATIONS, 12(1 (December 2021)) [10.1038/s41467-021-24876-1].

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

Beretta S.;Norelli M.;Merelli I.;
2021

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.
Articolo in rivista - Articolo scientifico
Animals; Bone Marrow; Cell Cycle Checkpoints; Chronic Disease; Cyclin-Dependent Kinase Inhibitor p16; Gene Expression Regulation; Green Fluorescent Proteins; Hematopoiesis; Hematopoietic Stem Cells; Histiocytosis; Humans; Inflammation; Lentivirus; Mice; Mutation; Myeloid Cells; Paracrine Communication; Principal Component Analysis; Proto-Oncogene Proteins B-raf; Tumor Necrosis Factor-alpha; Cellular Senescence; Oncogenes
English
27-lug-2021
2021
12
1 (December 2021)
4559
none
Biavasco, R., Lettera, E., Giannetti, K., Gilioli, D., Beretta, S., Conti, A., et al. (2021). Oncogene-induced senescence in hematopoietic progenitors features myeloid restricted hematopoiesis, chronic inflammation and histiocytosis. NATURE COMMUNICATIONS, 12(1 (December 2021)) [10.1038/s41467-021-24876-1].
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/324825
Citazioni
  • Scopus 20
  • ???jsp.display-item.citation.isi??? 21
Social impact