BRAF-mutant hematopoietic malignancies

Mutations activating the serine-threonine kinase BRAF have been identified in a variety of cancers since they were first described in 2002. Currently, it is estimated that BRAF is mutated in ~8% of all cancers [1]. Sequencing studies performed in a broad spectrum of hematologic malignancies have revealed that mutations in BRAF, although generally quite rare amongst leukemias and lymphomas, are strikingly enriched in 2 rare hematologic malignancies: hairy cell leukemia (HCL) and the systemic histiocytoses, Langerhans Cell Histiocytosis (LCH) and Erdheim-Chester Disease (ECD) (Figure). Although the discovery of the high frequency BRAFV600E mutations in these conditions has encouraged the intiation of novel therapeutic strategies targeting BRAFV600E, they have also provided unexpected biological insights through investigation of the functional consequence of BRAFV600E. One issue addressed is the cell-of-origin in HCL and the histiocytoses, a debate that had remained unresolved for decades. While LCH has been proposed to arise from epidermal Langerhans cells or immature myeloid dendritic cell (DC) precursors, HCL has largely been considered to be a mature B cell malignancy, despite the fact that their immunophenotype and morphology are distinct from any known normal B cell population. The recent discovery of BRAFV600E mutations in nearly 100% of HCL patients and 40-60% of LCH patients led our group [2; 3] and a group led by Drs. Miriam Merad and Carl Allen [4] to investigate the cellof-origin in HCL and LCH by identifying cell populations in which the BRAFV600E mutation could be found. Our studies showed that the BRAFV600E mutation is present in highly purified long-term hematopoietic stem cells (LTHSCs; lineage-negative CD34+ CD38CD90+ CD45RAcells) from HCL patients. Moreover, xenotransplantation of purified LT-HSCs from BRAFV600E mutant HCL patients gave rise to stable human grafts that propagated the BRAFV600E mutation. Berres et al. similarly identified the BRAFV600E mutation in CD34+ cells from LCH patients with multisystem disease by sequencing of purified cells as well as colonies derived from CD34+ cells from LCH patients grown in methycellulose (Figure). The presence of the BRAFV600E mutation in hematopoietic stem/progenitor cells (HSPCs) of patients with seemingly disparate clinical disorders raises the question of the importance of such mutations in HSPCs. In the case of LCH, Berres et al. posited a disease pathogenesis model in which the cell-of-origin of the BRAFV600E mutation defines the extent and severity of the clinical disease (Figure). Thus, delineation of the precise HSPC that the BRAFV600E mutation arises in may provide further insights into how LCH relates to HCL. Similar studies of the related, but clinically distinct, histiocytic disorder ECD may be likewise enlightening. Functional evidence of whether BRAFV600E mutant CD34+ cells from LCH patients are capable of selfrenewal in vivo in xenograft assays may also provide further insights about the HSPC compartment of these Editorial