Biological and clinical significance of somatic mutations in Langerhans cell histiocytosis and related histiocytic neoplastic disorders

C. E. Allen, D. W. Parsons
2015 Hematology ASH Education Program  
Langerhans cell histiocytosis (LCH), juvenile xanthogranuloma (JXG), and Erdheim-Chester disease (ECD) represent histiocytic disorders with a wide range of clinical manifestations. Until recently, mechanisms of pathogenesis have been speculative and debate has focused on classification of these conditions as reactive versus neoplastic. Genomic studies have been challenged by scarce tissue specimens, as well as heterogeneous nature of the lesions with variable infiltration of pathologic
more » ... pathologic histiocytes. Whole-exome sequencing recently revealed a very low frequency of somatic mutations in LCH, JXG, and ECD compared to other neoplastic disorders. However, at least in the cases of LCH and ECD, there is a very high frequency of activating mutations in MAPK pathway genes, most notably BRAF-V600E, as well as MAP2K1, in LCH and NRAS in ECD. In ECD, recurrent mutations in the PI3K pathway gene PIK3CA have also been described. The heterogeneous clinical manifestations of these disorders may therefore be the cumulative result of activation of MAPK mutations (along with modifying signals from other pathways) at distinct stages of myeloid differentiation. Implications of this model include redefinition of LCH, JXG, and ECD as a group of clinically diverse myeloid neoplastic disorders with a common mechanism of pathogenesis. This model supports refocusing therapeutic strategies for these diseases on a personalized approach based on specific mutations and the cell(s) of origin. Learning Objectives • To understand the biological significance of recurrent somatic mutations in LCH, JXG, and ECD • To evaluate models of pathogenesis of LCH, JXG, and ECD based on emerging genomic and biological data • To develop therapeutic approaches for patients with LCH, JXG, and ECD in light of new models of pathogenesis
doi:10.1182/asheducation-2015.1.559 pmid:26637772 fatcat:4v3m77zbrfbk5o3u2oopydjwcy