Introduction
Histiocytic neoplasms are a diverse group of clonal hematopoietic disorders that are driven by mutations activating the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinases (PI3K) pathways1-3. While BRAF -V600E is the most common alteration in histiocytic neoplasms, multiple alternate pathway activating mechanisms have been described, including MAP2K1 ,ARAF , PIK3CA , NRAS , and KRAS mutations as well as BRAF , ALK, and NTRK1fusions1-3. BRAF-fusions previously reported in cases of histiocytic neoplasms1,4-7 were found to contain the N-terminal region of another gene (often of unclear significance) joined to the BRAF kinase domain (including exons 9-18 or 11-18), resulting in the loss of the BRAF N-terminal regulatory RAS-binding regions (exons 1-8). Despite the prevalence of BRAF-alterations in histiocytic tumors, to date there have been no detailed molecular investigations comparing BRAF-fusions found in distinct sub-types of histiocytic neoplasms and only one study explored responsiveness of BRAF-fusions to single-agent RAF-therapies4. To address this, we present two pediatric histiocytosis cases, with distinct pathologic features and clinical behavior, each harboring a BRAF-fusion identified by next-generation sequencing (Supplemental Methods and Table S1) and study their in vitro responsiveness to RAF-targeted inhibitors.