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Pigment Cell Melanoma Res. 2015 Jul;28(4):407-16. doi: 10.1111/pcmr.12369. Epub 2015 Apr 22.

NF1 loss induces senescence during human melanocyte differentiation in an iPSC-based model.

Author information

1
Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.
2
Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany.
3
Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center (DKFZ), Heidelberg, Germany.
4
Division of Translational Immunology, German Cancer Research Center (DKFZ) and National Center of Tumor Diseases (NCT), Heidelberg, Germany.
5
Department of Dermatology, Ghent University Hospital, Ghent, Belgium.
6
Institute of Human Genetics, University of Ulm, Ulm, Germany.
7
INSERM U1065 (Team 1), C3M, Biology and Pathologies of melanocytes, Nice, France.

Abstract

Neurofibromatosis type 1 (NF1) is a frequent genetic disease leading to the development of Schwann cell-derived neurofibromas or melanocytic lesions called café-au-lait macules (CALMs). The molecular mechanisms involved in CALMs formation remain largely unknown. In this report, we show for the first time pathophysiological mechanisms of abnormal melanocyte differentiation in a human NF1(+/-) -induced pluripotent stem cell (iPSC)-based model. We demonstrate that NF1 patient-derived fibroblasts can be successfully reprogrammed in NF1(+/-) iPSCs with active RAS signaling and that NF1 loss induces senescence during melanocyte differentiation as well as in patient's-derived CALMs, revealing a new role for NF1 in the melanocyte lineage.

KEYWORDS:

café-au-lait macules; induced pluripotent stem cell; melanocyte; neurofibromatosis type 1; oncogene-induced senescence

PMID:
25824590
DOI:
10.1111/pcmr.12369
[Indexed for MEDLINE]

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