TY - JOUR
T1 - Cooperation of Gata3, c-Myc and Notch in malignant transformation of double positive thymocytes
AU - van Hamburg, Jan Piet
AU - de Bruijn, Marjolein J.W.
AU - Dingjan, Gemma M.
AU - Beverloo, H. Berna
AU - Diepstraten, Hans
AU - Ling, Kam Wing
AU - Hendriks, Rudi W.
N1 - Funding Information: We would like to thank T. Schonewille, E. de Haas, E. Splinter and E. van Drunen (Erasmus MC Rotterdam) for assistance at various stages of the project. This work was partly supported by the Dutch Cancer Society and the International Association of Cancer Research.
PY - 2008/6
Y1 - 2008/6
N2 - 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.
AB - 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.
KW - Expression profiling
KW - Gata3
KW - Lymphoma
KW - T cell
KW - c-Myc
UR - http://www.scopus.com/inward/record.url?scp=43449100337&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.molimm.2008.03.018
DO - https://doi.org/10.1016/j.molimm.2008.03.018
M3 - Article
C2 - 18471881
SN - 0161-5890
VL - 45
SP - 3085
EP - 3095
JO - Molecular immunology
JF - Molecular immunology
IS - 11
ER -