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.
journal_name
Haematologicajournal_title
Haematologicaauthors
Mathur R,Sehgal L,Havranek O,Köhrer S,Khashab T,Jain N,Burger JA,Neelapu SS,Davis RE,Samaniego Fdoi
10.3324/haematol.2016.144964subject
Has Abstractpub_date
2017-02-01 00:00:00pages
373-380issue
2eissn
0390-6078issn
1592-8721pii
haematol.2016.144964journal_volume
102pub_type
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