| Literature DB >> 27742770 |
Rohit Mathur1, Lalit Sehgal1, Ondrej Havranek1, Stefan Köhrer2, Tamer Khashab1, Neeraj Jain1, Jan A Burger2, Sattva S Neelapu1, R Eric Davis1, Felipe Samaniego3.
Abstract
Histone methylation and demethylation regulate B-cell development, and their deregulation correlates with tumor chemoresistance in diffuse large B-cell lymphoma, limiting cure rates. Since histone methylation status correlates with disease aggressiveness and relapse, we investigated the therapeutic potential of inhibiting histone 3 Lys27 demethylase KDM6B, in vitro, using the small molecule inhibitor GSK-J4. KDM6B is overexpressed in the germinal center B-cell subtype of diffuse large B-cell lymphoma, and higher KDM6B levels are associated with worse survival in patients with diffuse large B-cell lymphoma treated with R-CHOP. GSK-J4-induced apoptosis was observed in five (SU-DHL-6, OCI-Ly1, Toledo, OCI-Ly8, SU-DHL-8) out of nine germinal center B-cell diffuse large B-cell lymphoma cell lines. Treatment with GSK-J4 predominantly resulted in downregulation of B-cell receptor signaling and BCL6. Cell lines expressing high BCL6 levels or CREBBP/EP300 mutations were sensitive to GSK-J4. Our results suggest that B-cell receptor-dependent downregulation of BCL6 is responsible for GSK-J4-induced cytotoxicity. Furthermore, GSK-J4-mediated inhibition of KDM6B sensitizes germinal center B-cell diffuse large B-cell lymphoma cells to chemotherapy agents that are currently utilized in treatment regimens for diffuse large B-cell lymphoma. Copyright© Ferrata Storti Foundation.Entities:
Mesh：
Substances：
Year: 2016 PMID： 27742770 PMCID： PMC5286945 DOI： 10.3324/haematol.2016.144964
Source DB: PubMed Journal: Haematologica ISSN： 0390-6078 Impact factor: 9.941