The role of wild type and mutant STAT6 in the regulation of the BCL6 promoter in primary mediastinal B cell and classical Hodgkin lymphoma
Final Report Abstract
In this project we focused our work on the role of two transcription factors and their interplay in PMBL and cHL. Our investigations revealed the new molecular characteristic of PMBL, the recurrent STAT6 mutation within the DNA-binding domain. Moreover, PMBL does not share this property with cHL like several other molecular characteristics. We showed that PMBL harbour intratumoral heterogeneity, which also play a role in the transcriptiona regulation of at least two factors, STAT6 and BCL6. Additionally, we suggest a new therapeutic way for PMBL treatment based on the heterogeneous nature of these tumors and mutual exclusive expression of transcription factors STAT6 and BCL6, which are necessary for the PMBL proliferation. Interestingly, the STAT6 DNA –binding domain mutations (36% of primary PMBLs harbor these mutations) do not provide PMBL tumors obvious advantage in most physiological aspects, like proliferation, apoptosis induction, ROS production and others. On the other hand, these mutations seem to be a reason for changes in the intratumoral heterogeneity structur of PMBL. Moreover, STAT6 mutations may be a reason for sensitization of PMBL cells to the treatment with JAK-Inhibitor, which reduce the STAT6 activity by decrease of its phosphorylation. Our publication of Häberle et al., in Oncoscience 2014 resulted in the great discussion regarding the role of the combination of chemotherapy and targeted treatment vs. high dosis chemotherapy for PMBL patients.
