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Alternative genetic mechanisms of BRAF activation in Langerhans cell histiocytosis.

Authors :
Chakraborty R
Burke TM
Hampton OA
Zinn DJ
Lim KP
Abhyankar H
Scull B
Kumar V
Kakkar N
Wheeler DA
Roy A
Poulikakos PI
Merad M
McClain KL
Parsons DW
Allen CE
Source :
Blood [Blood] 2016 Nov 24; Vol. 128 (21), pp. 2533-2537. Date of Electronic Publication: 2016 Oct 11.
Publication Year :
2016

Abstract

Langerhans cell histiocytosis (LCH) is characterized by inflammatory lesions containing pathologic CD207 <superscript>+</superscript> 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 <superscript>+</superscript> 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.<br /> (© 2016 by The American Society of Hematology.)

Details

Language :
English
ISSN :
1528-0020
Volume :
128
Issue :
21
Database :
MEDLINE
Journal :
Blood
Publication Type :
Academic Journal
Accession number :
27729324
Full Text :
https://doi.org/10.1182/blood-2016-08-733790