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.