Histone methylation and demethylation regulates B-cell development, and their deregulation correlates with tumor chemoresistance in diffuse large B-cell lymphoma, limiting curative 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 DLBCL germinal center B-cell subtype, and higher KDM6B levels are associated with worse survival in DLBCL patients 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 GCB-DLBCL cell lines. Treatment with GSK-J4 predominantly resulted in downregulation of BCR signaling and Bcl6. Cell lines expressing high Bcl6 levels or CREBBP/EP300 mutations were sensitive to GSK-J4. Our results suggest that BCR dependent downregulation of Bcl6 is responsible for GSK-J4-induced cytotoxicity. Further, GSK-J4 mediated inhibition of KDM6B sensitizes GCB-DLBCL cells to chemotherapy agents that are currently utilized in DLBCL treatment regimens.
- Received March 7, 2016.
- Accepted October 4, 2016.
- Copyright © 2016, Ferrata Storti Foundation