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Blood, 1 April 2007, Vol. 109, No. 7, pp. 3015-3023.
Prepublished online as a Blood First Edition Paper on December 5, 2006; DOI 10.1182/blood-2006-08-044347.
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Submitted August 30, 2006
Accepted November 18, 2006
Comprehensive analysis of homeobox genes in hodgkin lymphoma cell lines identifies dysregulated expression of HOXB9 mediated via ERK5 signaling and BMI1
Stefan Nagel*, Christof Burek, Letizia Venturini, Michaela Scherr, Hilmar Quentmeier, Corinna Meyer, Andreas Rosenwald, Hans G. Drexler, and Roderick A.F. MacLeod
Human and Animal Cell Cultures, DSMZ, Braunschweig, Germany
Institute of Pathology, University of Wurzburg, Wurzburg, Germany
Dept of Hematology, Hemostatis & Oncology, Hannover Medical School, Hannover, Germany
* Corresponding author; email: sna{at}dsmz.de.
Many members of the nearly 200-strong homeobox gene family have been implicated in cancer, mostly following ectopic expression. In this study we analyzed homeobox gene expression in Hodgkin lymphoma (HL) cell lines. Both reverse transcription-polymerase chain reaction (RT-PCR) using degenerate primers and microarray profiling identified consistently upregulated HOXB9 expression. Analysis of HOXB9 regulation in HL cells revealed E2F3A and BMI1 as activator and repressor, respectively. Furthermore, a constitutively active ERK5 pathway was identified in all HL cell lines analyzed as well as primary HL cells. Our data show that ERK5 probably mediates HOXB9 expression by repressing BMI1. Additionally, expression analysis of the neighboring microRNA gene mir-196a1 revealed coregulation with HOXB9. Functional analysis of HOXB9 by knockdown and overexpression assays indicated their influence on both proliferation and apoptosis in HL cells. In summary, we identified upregulation of HOXB9 in HL mediated by constitutively active ERK5 signaling which may represent novel therapeutic targets in HL.
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