The role of wild type and mutant STAT6 in the regulation of the BCL6 promoter in primary mediastinal B cell and classical Hodgkin lymphoma

• Applicant: Dr. Olga Ritz
• Subject Area: Pathology
• Term: from 2008 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 60331643

Primary mediastinal B-cell Lymphoma (PMBL) is a distinct subtype of diffuse large Bcell lymphoma (DBLCL) exibiting constitutively activated Signal Transducer and Activator of Transcription (STAT) 6. Our recent work revealed that MedB-1, a PMBLderived cell line, and Hodgkin-derived cell line L1236 and 20 of 55 (36%) PMBL cases harbour heterozygous missense mutations in the STAT6 DNA binding domain, whereas no such mutation was found in 25 DBLCL samples. The mutant STAT6 proteins showed a decreased DNA binding ability in transfected HEK293 cells, but no decrease in expression of STAT6 canonical target genes was observed in PMBL cases with a mutated STAT6 gene. Therefore I would like to address the question if these mutations, which affect the region involved in DNA recognition element, permits the recruitment of STAT6 on non-canonical STAT6 GAS sites, that drive the expression of potential oncogenes and, therefore, might participate in lymphomagenesis. We further observed that both, PMBL and Hodgkin derived cell lines, show the presence of the p-STAT6 and BCL6 in the nuclei and that the distribution of these two factors is mutually exclusive in PMBL cell lines. Additionally, I have first experimental indications that p-STAT6 regulates one of two expressed BCL6 mRNA (called short transcript) in PMBL and Hodgkin cell lines. Consequently, this work will characterize in detail the role of wild type (wt) and mutated STAT6 in the transcriptional regulation of BCL6 short transcript in PMBL and cHL. Moreover, the general analysis of possible new target genes regulated by mutated STAT6 will help to understand the function of STAT6 mutations in cancer and might reveal new, potentially therapeutic targets.

• DFG Programme: Research Grants