The Interplay of BRAF and Ras/MAPK Pathways Inducing Senescence in Langerhans Cells Histiocytosis

Abstract

A rare disease characterized by aberrant function, divergence, and uncontrolled proliferation of mononuclear phagocyte cells, Langerhans histiocytosis, and its concomitant granulomatous lesions within histiocytes can occur in any organ but has a rapport for the skin, bone, and the lungs. While it is known that somatic mutations in the MAPK pathway, specifically BRAF^V600, are common in most LCH cases within LCH lesions, the mechanisms underpinning BRAF^V600 mutation progenitor cells and its consequence of LCH lesions are wholly indefinite. Furthermore, gene expression between epidermal Langerhans cells and CD207+ lesional cells of LCH share a consistent signature parallel with immature myeloid precursors in LCH cells, implying a basis for hematopoietic provenance of such cells. So, while LCH is likely a result of clonally expanding neoplasm, the question remains if Langerhans cells are truly normal cells responding to immune signals gone awry or if it is an actual anomalous variant. Recent findings have illuminated the BRAFV600E mutation and its ability to influence multipotent hematopoietic cells in LCH disease. Scientists discovered the expression of the BRAF^V600E mutation guides to a senescence program that results in growth arrest in hematopoietic progenitor cells, anti-apoptosis, and a secretory phenotype in mice that leads to the growth of LCH lesions. Conversely, the ablation of these senescent cells via induced apoptosis and SASP inhibitors ameliorated LCH disease in mice. Such results allude to senescent cells being a target that can potentially advance LCH treatment.