Cooperation of Gata3, c-Myc and Notch in malignant transformation of double positive thymocytes

Jan piet Hamburg, Marjolein De Jong - de Bruijn, Gemma Dingjan, Berna Beverloo, H Diepstraten, KW (Kam-Wing) Ling, Rudi Hendriks

Research output: Contribution to journalArticleAcademicpeer-review

22 Citations (Scopus)

Abstract

Gata transcription factors are critical regulators of proliferation and differentiation implicated in various human cancers, but specific genes activated by Gata proteins remain to be identified. We previously reported that enforced expression of Gata3 during T cell development in CD2-Gata3.transgenic mice induced CD4(+)CD8(+) double-positive (DP) T cell lymphoma. Here, we show that the presence of the DO11.10 T-cell receptor transgene, which directs DP cells towards the CD4 lineage, resulted in enhanced lymphoma development and a dramatic increase in thymocyte cell size in CD2-Gata3 transgenic mice. CD2-Gata3 DP cells expressed high levels of the proto-oncogene c-Myc but the Notch1 signaling pathway, which is known to induce c-Myc, was not activated. Gene expression profiling showed that in CD2-Gata3 lymphoma cells transcription of c-Myc and its target genes was further increased. A substantial fraction of CD2-Gata3 lymphomas had trisomy of chromosome 15, leading to an increased c-Myc gene dose. Interestingly, most lymphomas showed high expression of the Notch targets Deltex1 and Hes1, often due to activating Notch1 PEST domain mutations. Therefore, we conclude that enforced Gata3 expression converts DP thymocytes into a pre-malignant state, characterized by high c-Myc expression, whereby subsequent induction of Notch1 signaling cooperates to establish malignant transformation. The finding that Gata3 regulates c-Myc expression levels, in a direct or indirect fashion, may explain the parallel phenotypes of mice with overexpression or deficiency of either of the two transcription factors. (C) 2008 Elsevier Ltd. All rights reserved.
Original languageUndefined/Unknown
Pages (from-to)3085-3095
Number of pages11
JournalMolecular Immunology
Volume45
Issue number11
DOIs
Publication statusPublished - 2008

Cite this