BRAFV600E-induced senescence drives Langerhans Cell Histiocytosis pathophysiology

Langerhans cell histiocytosis (LCH) is a potentially fatal condition characterized by granulomatous lesions with characteristic clonal mononuclear phagocytes (MNP) harboring activating somatic mutations in MAPK pathway genes, most notably BRAFV600E. We recently discovered that the BRAFV600E mutation can also affect multipotent hematopoietic progenitor cells (HPC) in multisystem LCH disease. How BRAFV600E mutation in HPC leads to LCH is not known. Here we show that enforced expression of the BRAFV600E mutation in early mouse and human multipotent HPC induced a senescence program that led to HPC growth arrest, apoptosis resistance and senescence-associated secretory phenotype (SASP). SASP, in turn, promoted HPC skewing towards the MNP lineage leading to the accumulation of senescent MNP in tissue and the formation of LCH lesions. Accordingly, elimination of senescent cells using INK-ATTAC transgenic mice as well as pharmacologic blockade of SASP improved LCH disease in mice. These results identify senescent cells as a novel target for the treatment of LCH.