Mutually exclusive recurrent somatic mutations in MAP2K1 and BRAF support a central role for ERK activation in LCH pathogenesis.

TitleMutually exclusive recurrent somatic mutations in MAP2K1 and BRAF support a central role for ERK activation in LCH pathogenesis.
Publication TypeJournal Article
Year of Publication2014
AuthorsChakraborty, R, Hampton, OA, Shen, X, Simko, SJ, Shih, A, Abhyankar, H, Lim, KPhaik Har, Covington, KR, Treviño, L, Dewal, N, Muzny, DM, Doddapaneni, H, Hu, J, Wang, L, Lupo, PJ, M Hicks, J, Bonilla, DL, Dwyer, KC, Berres, M-L, Poulikakos, PI, Merad, M, McClain, KL, Wheeler, DA, Allen, CE, D Parsons, W
JournalBlood
Volume124
Issue19
Pagination3007-15
Date Published2014 Nov 6
ISSN1528-0020
KeywordsDendritic Cells, Disease Progression, Erdheim-Chester Disease, HEK293 Cells, Histiocytosis, Langerhans-Cell, Histiocytosis, Sinus, Humans, MAP Kinase Kinase 1, MAP Kinase Signaling System, Mutation, Missense, Proto-Oncogene Proteins B-raf, Xanthogranuloma, Juvenile
Abstract

Langerhans cell histiocytosis (LCH) is a myeloproliferative disorder characterized by lesions composed of pathological CD207(+) dendritic cells with an inflammatory infiltrate. BRAFV600E remains the only recurrent mutation reported in LCH. In order to evaluate the spectrum of somatic mutations in LCH, whole exome sequencing was performed on matched LCH and normal tissue samples obtained from 41 patients. Lesions from other histiocytic disorders, juvenile xanthogranuloma, Erdheim-Chester disease, and Rosai-Dorfman disease were also evaluated. All of the lesions from histiocytic disorders were characterized by an extremely low overall rate of somatic mutations. Notably, 33% (7/21) of LCH cases with wild-type BRAF and none (0/20) with BRAFV600E harbored somatic mutations in MAP2K1 (6 in-frame deletions and 1 missense mutation) that induced extracellular signal-regulated kinase (ERK) phosphorylation in vitro. Single cases of somatic mutations of the mitogen-activated protein kinase (MAPK) pathway genes ARAF and ERBB3 were also detected. The ability of MAPK pathway inhibitors to suppress MAPK kinase and ERK phosphorylation in cell culture and primary tumor models was dependent on the specific LCH mutation. The findings of this study support a model in which ERK activation is a universal end point in LCH arising from pathological activation of upstream signaling proteins.

DOI10.1182/blood-2014-05-577825
Alternate JournalBlood
PubMed ID25202140
PubMed Central IDPMC4224195
Grant ListP30 CA016672 / CA / NCI NIH HHS / United States
R01 CA154489 / CA / NCI NIH HHS / United States
R01 CA154947 / CA / NCI NIH HHS / United States
P30CA125123 / CA / NCI NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States
P50 CA126752 / CA / NCI NIH HHS / United States
P50CA126752 / CA / NCI NIH HHS / United States
P30 CA125123 / CA / NCI NIH HHS / United States
R01 CA154947A / CA / NCI NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
K12 CA090433 / CA / NCI NIH HHS / United States
U01 AI095611 / AI / NIAID NIH HHS / United States
AI10008 / AI / NIAID NIH HHS / United States
AI089987 / AI / NIAID NIH HHS / United States
R01 CA173861 / CA / NCI NIH HHS / United States
T32 GM088129 / GM / NIGMS NIH HHS / United States
U19 AI089987 / AI / NIAID NIH HHS / United States