Alternative genetic mechanisms of BRAF activation in Langerhans cell histiocytosis.

TitleAlternative genetic mechanisms of BRAF activation in Langerhans cell histiocytosis.
Publication TypeJournal Article
Year of Publication2016
AuthorsChakraborty, R, Burke, TM, Hampton, OA, Zinn, DJ, Lim, KPhaik Har, Abhyankar, H, Scull, B, Kumar, V, Kakkar, N, Wheeler, DA, Roy, A, Poulikakos, PI, Merad, M, McClain, KL, D Parsons, W, Allen, CE
Date Published2016 Nov 24

Langerhans cell histiocytosis (LCH) is characterized by inflammatory lesions containing pathologic CD207(+) dendritic cells with constitutively activated ERK. Mutually exclusive somatic mutations in MAPK pathway genes have been identified in ∼75% of LCH cases, including recurrent BRAF-V600E and MAP2K1 mutations. To elucidate mechanisms of ERK activation in the remaining 25% of patients, we performed whole-exome sequencing (WES, n = 6), targeted BRAF sequencing (n = 19), and/or whole-transcriptome sequencing (RNA-seq, n = 6) on 24 LCH patient samples lacking BRAF-V600E or MAP2K1 mutations. WES and BRAF sequencing identified in-frame BRAF deletions in the β3-αC loop in 6 lesions. RNA-seq revealed one case with an in-frame FAM73A-BRAF fusion lacking the BRAF autoinhibitory regulatory domain but retaining an intact kinase domain. High levels of phospho-ERK were detected in vitro in cells overexpressing either BRAF fusion or deletion constructs and ex vivo in CD207(+) cells from lesions. ERK activation was resistant to BRAF-V600E inhibition, but responsive to both a second-generation BRAF inhibitor and a MEK inhibitor. These results support an emerging model of universal ERK-activating genetic alterations driving pathogenesis in LCH. A personalized approach in which patient-specific alterations are identified may be necessary to maximize benefit from targeted therapies for patients with LCH.

Alternate JournalBlood
PubMed ID27729324
PubMed Central IDPMC5123197
Grant ListR01 CA154489 / CA / NCI NIH HHS / United States
R01 CA154947 / CA / NCI NIH HHS / United States
R01 CA190400 / CA / NCI NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States
P50 CA126752 / CA / NCI NIH HHS / United States
P30 CA125123 / CA / NCI NIH HHS / United States
R01 CA173861 / CA / NCI NIH HHS / United States