STAT6-mediated BCL6 repression in primary mediastinal B-cell lymphoma (PMBL)
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Olga Ritz1, Karolin Rommel2, Karola Dorsch1, Elena Kelsch1, Julia Melzner1, Michaela Buck1, Karen Leroy3, Vasiliki Papadopoulou4, Simon Wagner4, Ralf Marienfeld1, Silke Brüderlein1, Jochen K. Lennerz,1 and Peter Möller1
1 Institute of Pathology, University Ulm, Ulm, Germany
2 Institute for Research in Biomedicine, Bellinzona, Switzerland
3 INSERM, U955, and Université Paris Est Créteil, Hôpital Henri Mondor, AP-HP, Département de Pathologie, Créteil, France
4 Department of Cancer Studies and Molecular Medicine and MRC Toxicology Unit, University of Leicester, Leicester, UK
Peter Möller, email:
Keywords: PMBL, intratumoral heterogeneity, BCL6, pSTAT6
Received: July 1, 2013 Accepted: July 11, 2013 Published: July 13, 2013
Primary mediastinal B-cell lymphoma (PMBL) is characterized by aberrant activation of JAK/STAT-signaling resulting in constitutive presence of phosphorylated STAT6 (pSTAT6). In primary PMBL samples pSTAT6 is only expressed in a sub-population of lymphoma cells in a pattern that is reminiscent of that of the BCL6 oncogene. Double-fluorescence staining was carried out to determine the association between these two proteins in ten primary PMBL cases and three available PMBL cell line models. Surprisingly, only a minute fraction of double-positive nuclei was observed, while each sample contained considerable fractions of single-positive pSTAT6 and BCL6 nuclei. The intratumoral coexistence of BCL6+/pSTAT6- and BCL6-/pSTAT6+ subpopulations suggests a negative interaction between these factors. In silico screening of the STAT6 /BCL6 promoters for DNA consensus binding sites identified five STAT-binding-sites in the BCL6 promoter. We confirmed STAT6 binding to the BCL6 promoter in vitro and in vivo by band shift / super shift assays and chromatin immunoprecipitations. Using BCL6 luciferase reporter assays, depletion of STAT6 by siRNA, and ectopic overexpression of a constitutive active STAT6 mutant, we proved that pSTAT6 is sufficient to transcriptionally repress BCL6. Recently developed small molecule inhibitors 79-6 and TG101348 that increases BCL6 target gene expression and decreases pSTAT6 levels, respectively, demonstrate that a combined targeting results in additive efficacy regarding their negative effect on cell viability.
The delineated pSTAT6-mediated molecular repression mechanism links JAK/STAT to BCL6-signaling in PMBL and may carry therapeutic potential.
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