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

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

doi:10.1038/s41467-021-24876-1

Abstract

ABSTRACTActivating 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.

Highlights

Activating mutations in the BRAF-MAPK pathway have been reported in histiocytoses, hematological inflammatory neoplasms characterized by multi-organ dissemination of proinflammatory myeloid cells
BRAFV600E activation in human hematopoietic stem and progenitor cells (HSPCs) leads to lethal bone marrow aplasia and histiocytosis
The median time of disease onset was dependent on the proportion of BRAFV600E-expressing cells since mice transplanted with 30% of BRAFV600E-expressing cells

Summary

Introduction

Activating mutations in the BRAF-MAPK pathway have been reported in histiocytoses, hematological inflammatory neoplasms characterized by multi-organ dissemination of proinflammatory myeloid cells. Several genetically engineered mouse models of BrafV600E expression in pan or restricted hematopoietic cell lineages have shown a spectrum of diverse phenotypes ranging from histiocytosis-like disease to HCL12,13. These mouse models do not fully recapitulate the heterogeneity observed in human histiocytic lesions and did not provide mechanistic insights on the role of OIS on disease etiology and progression. Mice developed aggressive histiocytosis with multi-systemic infiltration of senescent macrophages and dendritic cells characterized by an activated inflammatory program sustained by senescence-associated cytokines. Our findings establish a paradigm of pathogenesis of high-risk inflammatory neoplasms in which disease onset is preceded by the establishment of OIS in human hematopoiesis and point to the innovative therapeutic potential of senescence modulation for disease treatment

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