Phox2B mutations and the Delta–Notch pathway in neuroblastoma

van Limpt, Vera; Chan, Alvin; Schramm, Alexander; Eggert, Angelika; Versteeg, Rogier

doi:10.1016/j.canlet.2005.02.050

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Volume 228, Issue 1 , Pages 59-63, 18 October 2005

Phox2B mutations and the Delta–Notch pathway in neuroblastoma

Vera van Limpt
- Department of Human Genetics, Academic Medical Center, University of Amsterdam, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands
Alvin Chan
- Department of Human Genetics, Academic Medical Center, University of Amsterdam, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands
Alexander Schramm
- Department of Oncology/Hematology and Endocrinology, University Children's Hospital Essen, Hufelandstrs. 55, 45122 Essen, Germany
Angelika Eggert
- Department of Oncology/Hematology and Endocrinology, University Children's Hospital Essen, Hufelandstrs. 55, 45122 Essen, Germany
Rogier Versteeg
- Department of Human Genetics, Academic Medical Center, University of Amsterdam, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands
- Corresponding author. Tel.: +31 10 463 6691/2073; fax: +31 10 463 6801.

Received 3 January 2005; accepted 5 February 2005.

Abstract

We recently identified six neuroblastoma patients with constitutional or tumor-specific mutations in the homeobox gene Phox2B. Phox2B controls part of the differentiation program of the sympathetic nervous system (SNS). Mice with a homozygous inactivation of Phox2B fail in the proper differentiation of the chromaffin lineage of the SNS. Phox2B regulates HASH1 which can control expression of genes of the Delta–Notch pathway. We previously showed that a subset of neuroblastoma cell lines highly expresses Delta-like 1 (Dlk1), which is a marker for the chromaffin lineage of the SNS. Notch3 is expressed in another subset of neuroblastoma cell lines and marks tumors from an alternative differentiation lineage. Phox2B is also related to the TrkA differentiation pathway in neuroblastoma. Here we will review the role of Phox2B in differentiation programs of the SNS and in neuroblastoma pathogenesis.

Keywords: Neuroblastoma, Phox2B, Delta, Notch, Mutations