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

Rikhia Chakraborty, Oliver A. Hampton, Xiaoyun Shen, Stephen J. Simko, Albert Shih, Harshal Abhyankar, Karen Phaik Har Lim, Kyle R. Covington, Lisa Trevino, Ninad Dewal, Donna M. Muzny, Harshavardhan Doddapaneni, Jianhong Hu, Linghua Wang, Philip J. Lupo, M. John Hicks, Diana L. Bonilla, Karen C. Dwyer, Marie Luise Berres, Poulikos I. PoulikakosMiriam Merad, Kenneth L. McClain, David A. Wheeler, Carl E. Allen, D. Williams Parsons

Research output: Contribution to journalArticle

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 up stream signaling proteins.

Original languageEnglish (US)
Pages (from-to)3007-3015
Number of pages9
JournalBlood
Volume124
Issue number19
DOIs
StatePublished - Nov 6 2014
Externally publishedYes

Fingerprint

Langerhans Cell Histiocytosis
Extracellular Signal-Regulated MAP Kinases
Phosphorylation
Chemical activation
Mitogen-Activated Protein Kinases
Mutation
Mitogen-Activated Protein Kinase Kinases
Cell culture
Tumors
Genes
Tissue
Erdheim-Chester Disease
Juvenile Xanthogranuloma
Sinus Histiocytosis
Exome
Myeloproliferative Disorders
Primary Cell Culture
Mutation Rate
Missense Mutation
Protein Kinase Inhibitors

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Chakraborty, R., Hampton, O. A., Shen, X., Simko, S. J., Shih, A., Abhyankar, H., ... Parsons, D. W. (2014). Mutually exclusive recurrent somatic mutations in MAP2K1 and BRAF support a central role for ERK activation in LCH pathogenesis. Blood, 124(19), 3007-3015. https://doi.org/10.1182/blood-2014-05-577825

Mutually exclusive recurrent somatic mutations in MAP2K1 and BRAF support a central role for ERK activation in LCH pathogenesis. / Chakraborty, Rikhia; Hampton, Oliver A.; Shen, Xiaoyun; Simko, Stephen J.; Shih, Albert; Abhyankar, Harshal; Lim, Karen Phaik Har; Covington, Kyle R.; Trevino, Lisa; Dewal, Ninad; Muzny, Donna M.; Doddapaneni, Harshavardhan; Hu, Jianhong; Wang, Linghua; Lupo, Philip J.; Hicks, M. John; Bonilla, Diana L.; Dwyer, Karen C.; Berres, Marie Luise; Poulikakos, Poulikos I.; Merad, Miriam; McClain, Kenneth L.; Wheeler, David A.; Allen, Carl E.; Parsons, D. Williams.

In: Blood, Vol. 124, No. 19, 06.11.2014, p. 3007-3015.

Research output: Contribution to journalArticle

Chakraborty, R, Hampton, OA, Shen, X, Simko, SJ, Shih, A, Abhyankar, H, Lim, KPH, Covington, KR, Trevino, L, Dewal, N, Muzny, DM, Doddapaneni, H, Hu, J, Wang, L, Lupo, PJ, Hicks, MJ, Bonilla, DL, Dwyer, KC, Berres, ML, Poulikakos, PI, Merad, M, McClain, KL, Wheeler, DA, Allen, CE & Parsons, DW 2014, 'Mutually exclusive recurrent somatic mutations in MAP2K1 and BRAF support a central role for ERK activation in LCH pathogenesis', Blood, vol. 124, no. 19, pp. 3007-3015. https://doi.org/10.1182/blood-2014-05-577825
Chakraborty, Rikhia ; Hampton, Oliver A. ; Shen, Xiaoyun ; Simko, Stephen J. ; Shih, Albert ; Abhyankar, Harshal ; Lim, Karen Phaik Har ; Covington, Kyle R. ; Trevino, Lisa ; Dewal, Ninad ; Muzny, Donna M. ; Doddapaneni, Harshavardhan ; Hu, Jianhong ; Wang, Linghua ; Lupo, Philip J. ; Hicks, M. John ; Bonilla, Diana L. ; Dwyer, Karen C. ; Berres, Marie Luise ; Poulikakos, Poulikos I. ; Merad, Miriam ; McClain, Kenneth L. ; Wheeler, David A. ; Allen, Carl E. ; Parsons, D. Williams. / Mutually exclusive recurrent somatic mutations in MAP2K1 and BRAF support a central role for ERK activation in LCH pathogenesis. In: Blood. 2014 ; Vol. 124, No. 19. pp. 3007-3015.
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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 up stream signaling proteins.",
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T1 - Mutually exclusive recurrent somatic mutations in MAP2K1 and BRAF support a central role for ERK activation in LCH pathogenesis

AU - Chakraborty, Rikhia

AU - Hampton, Oliver A.

AU - Shen, Xiaoyun

AU - Simko, Stephen J.

AU - Shih, Albert

AU - Abhyankar, Harshal

AU - Lim, Karen Phaik Har

AU - Covington, Kyle R.

AU - Trevino, Lisa

AU - Dewal, Ninad

AU - Muzny, Donna M.

AU - Doddapaneni, Harshavardhan

AU - Hu, Jianhong

AU - Wang, Linghua

AU - Lupo, Philip J.

AU - Hicks, M. John

AU - Bonilla, Diana L.

AU - Dwyer, Karen C.

AU - Berres, Marie Luise

AU - Poulikakos, Poulikos I.

AU - Merad, Miriam

AU - McClain, Kenneth L.

AU - Wheeler, David A.

AU - Allen, Carl E.

AU - Parsons, D. Williams

PY - 2014/11/6

Y1 - 2014/11/6

N2 - 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 up stream signaling proteins.

AB - 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 up stream signaling proteins.

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