Activating Mutations in CSF1R and Additional Receptor Tyrosine Kinases in Sporadic and Familial Histiocytic Neoplasms

Genomic analyses of histiocytic neoplasms (including Langerhans Cell Histiocytosis (LCH) and the non-LCH Erdheim-Chester Disease (ECD)) have revolutionized our understanding of these disorders as clonal hematopoietic malignancies driven by MAPK signaling and led to FDA approval of vemurafenib for BRAFV600E-mutant ECD. Despite these advances, several questions about the pathogenesis of the histiocytoses remain unanswered. For example, the cell-of-origin of the histiocytoses is not definitively known. In addition, histiocytoses represent a spectrum of diseases, and genetic alterations across histiocytosis subtypes have not been comprehensively evaluated. Finally, although the histiocytoses most commonly occur as sporadic, non-hereditary disorders, familial clustering has been well documented and occurs most often in monozygotic twins. This has been taken to suggest a hereditary component of the disease, but germline genetic causes for histiocytoses are not known. Here we performed comprehensive genomic analyses of 218 patients with all subsets of histiocytoses, including monozygotic twins with histiocytosis. In so doing, we uncover a novel series of activating receptor tyrosine kinase (RTK) alterations in the histiocytoses, including the first example in any disease of recurrent, activating mutations in CSF1R, the RTK required for monocyte/macrophage development.We initially performed whole exome sequencing (WES) of skin lesions, blood, and fingernails from identical (monozygot...
Source: Blood - Category: Hematology Authors: Tags: 635. Myeloproliferative Syndromes: Basic Science: Identification of Novel Therapeutic Targets Source Type: research