Histiocytic neoplasms in the era of personalized genomic medicine.
Review
Overview
abstract
PURPOSE OF REVIEW: Since the discovery of B-Raf proto-oncogene (BRAF) V600E mutations in histiocytic neoplasms, diverse kinase alterations have been uncovered in BRAF V600E-wildtype histiocytoses. The purpose of this review is to outline recent molecular advances in histiocytic neoplasms and discuss their impact on the pathogenesis and treatment of these disorders. RECENT FINDINGS: Activating kinase alterations discovered in BRAF V600E-wildtype Langerhans (LCH) and non-Langerhans cell histiocytoses (non-LCH) result in constitutive activation of the mitogen-activated protein kinase and/or phosphoinositide 3-kinases-Akt murine thymoma pathways. These kinase alterations include activating mutations in A-Raf proto-oncogene, mitogen-activated protein kinase kinase 1, neuroblastoma rat sarcoma viral oncogene homolog, Kirsten rat sarcoma viral oncogene homolog, and phosphatidylinositol-4,5-bisphosphate 3 kinase, catalytic subunit α kinases in LCH and non-LCH; BRAF, anaplastic lymphoma receptor tyrosine kinase, and neurotrophic tyrosine kinase, receptor type 1 fusions, as well as the Ets variant 3-nuclear receptor coactivator 2 fusion in non-LCH; and mutations in the mitogen-activated protein kinase kinase kinase 1 and Harvey rat sarcoma viral oncogene homolog kinases in LCH and histiocytic sarcoma, respectively. These discoveries have refined the understanding of the histiocytoses as clonal, myeloid neoplasms driven by constitutive mitogen-activated protein kinase signaling and identified molecular therapeutic targets with promising clinical responses to rapidly accelerated fibrosarcoma and mitogen-activated protein kinase kinase inhibition. SUMMARY: Genomic analyses over the last 6 years have identified targetable kinase alterations in BRAF V600E-wildtype histiocytic neoplasms. However, despite this progress, the molecular pathogenesis and therapeutic responsiveness of non-BRAF V600E kinase alterations are still poorly defined in these disorders.
