Biology and genomics of LCH and related disorders

Abstract

The results of genomic analyses have provided a better understanding of the pathophysiology of the histiocytoses. This has been particularly relevant for the L Group histiocytoses, which include Langerhans cell histiocytosis (LCH), Erdheim-Chester disease (ECD), and indeterminate cell histiocytosis (ICH). Although the phenotype of LCH histiocytes is distinct from that of ECD histiocytes and the clinical presentations of the pure forms of each disease are different, they share many of the same genetic abnormalities. Approximately 50% of patients with LCH or ECD have activating somatic mutations of BRAF, and another 25% have activating mutations of MAP2K1, which encodes MEK1. The remaining LCH patients have mutations in NRAS, KRAS, or PIK3CA or no genomic abnormalities detected to date, although the ERK pathway is activated in those patients. The remaining ECD patients also have mutations in NRAS, KRAS, and PIK3CA. Translocations that produce fusion proteins which activate BRAF occur more frequently in ECD than in LCH. The presence of some of these activating mutations in circulating cells or in CD34+ bone marrow cells suggests that these diseases may arise from transforming events in early myeloid precursors. ICH cells do not carry these mutations but rather recurrent translocations. The driver status of BRAF and MAP2K1 mutations in LCH and ECD is supported by the clinical responses of patients with these mutations to the corresponding inhibitor drugs. Thus, the contemporary understanding is that these diseases are neoplasms of myeloid lineage cells accompanied by inflammatory cells.