FOXO1 downregulation contributes to the oncogenic program of primary mediastinal B-cell lymphoma
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Linka Xie1,2,*, Olga Ritz3,*, Frank Leithäuser3, Hanfeng Guan2,4, Johanna Färbinger2, Clarissa D. Weitzer2, Franziska Gehringer2, Silke Brüderlein3, Karlheinz Holzmann5, Marion J. Vogel2, Peter Möller3, Thomas Wirth2 and Alexey Ushmorov2
1 Cancer Center of Union Hospital, Tongji Medical College, HuaZhong University of Science and Technology, Wuhan, China
2 Institute of Physiological Chemistry, University of Ulm, Germany
3 Institute of Pathology, University of Ulm, Germany
4 Department of Orthopaedic Surgery, Tongji Hospital, Tongji Medical College, Hua Zhong University of Science and Technology, Wuhan, China
5 Genomics Core Facility University of Ulm, Germany
* These authors contributed equally to this work
Thomas Wirth, email:
Alexey Ushmorov, email:
Keywords: primary mediastinal B cell lymphoma, FOXO1, JAK2, BCL2L1/BCLxL, MYC
Received: February 1, 2014 Accepted: June 14, 2014 Published: June 15, 2014
Recently we have shown that the transcription factor FOXO1, highly expressed in B cells, is downregulated in classical Hodgkin lymphoma (cHL). As primary mediastinal B cell lymphoma (PMBL) has similarities with the cHL transcription program we investigated FOXO1 expression in this entity. By using immunohistochemistry we found that FOXO1 was absent or expressed at low levels in 19 of 20 primary PMBL cases. PMBL cell lines reproduce the low FOXO1 expression observed in primary cases. By analyzing gene expression profiling data we found that FOXO1 expression inversely correlated with JAK2 in PMBL cases. Targeting JAK2 activity by the small molecular weight inhibitor TG101348 resulted in upregulation of FOXO1 mRNA and protein expression in MedB-1 and U2940 cell lines, and the MYC inhibitor 10058-F4 increased FOXO1 mRNA in MedB-1 cells. Moreover, in MedB-1 cells FOXO1 expression was strongly upregulated by the inhibitor of DNA methylation 5-aza-2-deoxycytidine and by the histone deacetylase inhibitor trichostatin A. Since FOXO1 promoter was unmethylated, this effect is most likely indirect. FOXO1 activation in the FOXO1-negative MedB-1 cell line led to growth arrest and apoptosis, which was accompanied by repression of MYC and BCL2L1/BCLxL. Thus, FOXO1 repression might contribute to the oncogenic program and phenotype of PMBL.
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