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Blood. 2014 Nov 6;124(19):3007-15. doi: 10.1182/blood-2014-05-577825. Epub 2014 Sep 8.

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

Author information

1
Texas Children's Cancer Center, Texas Children's Hospital, Houston, TX;
2
Department of Molecular and Human Genetics, Human Genome Sequencing Center.
3
Texas Children's Cancer Center, Texas Children's Hospital, Houston, TX; Division of Pediatric Hematology-Oncology, Department of Pediatrics.
4
Texas Children's Cancer Center, Texas Children's Hospital, Houston, TX; Program in Translational Biology and Molecular Medicine, and.
5
Human Genome Sequencing Center.
6
Texas Children's Cancer Center, Texas Children's Hospital, Houston, TX; Division of Pediatric Hematology-Oncology, Department of Pediatrics, Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX;
7
Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX; and.
8
Department of Oncological Sciences, Tisch Cancer Institute, Immunology Institute, and.
9
Department of Oncological Sciences, Tisch Cancer Institute, Department of Dermatology, Icahn School of Medicine, New York, NY.
10
Texas Children's Cancer Center, Texas Children's Hospital, Houston, TX; Division of Pediatric Hematology-Oncology, Department of Pediatrics, Program in Translational Biology and Molecular Medicine, and.
11
Texas Children's Cancer Center, Texas Children's Hospital, Houston, TX; Department of Molecular and Human Genetics, Human Genome Sequencing Center, Division of Pediatric Hematology-Oncology, Department of Pediatrics, Program in Translational Biology and Molecular Medicine, and.

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.

PMID:
25202140
PMCID:
PMC4224195
DOI:
10.1182/blood-2014-05-577825
[Indexed for MEDLINE]
Free PMC Article

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