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Alternative genetic mechanisms of BRAF activation in Langerhans cell histiocytosis.
- 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.)
- Subjects :
- Adolescent
Adult
Aged
Child
Child, Preschool
Enzyme Activation genetics
Female
Histiocytosis, Langerhans-Cell enzymology
Humans
Infant
Male
Oncogene Proteins, Fusion metabolism
Protein Domains
Proto-Oncogene Proteins B-raf metabolism
Histiocytosis, Langerhans-Cell genetics
Mutation
Oncogene Proteins, Fusion genetics
Proto-Oncogene Proteins B-raf genetics
Subjects
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