title: Inhibition of demethylase KDM6B sensitizes diffuse large B-cell lymphoma to chemotherapeutic drugs.
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.
authors.affiliation: Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center.
authors.forename: Rohit
authors.initials: R
authors.lastname: Mathur
authors.affiliation: Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center.
authors.forename: Lalit
authors.initials: L
authors.lastname: Sehgal
authors.affiliation: Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center.
authors.forename: Ondrej
authors.initials: O
authors.lastname: Havranek
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Köhrer
authors.affiliation: Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center.
authors.forename: Tamer
authors.initials: T
authors.lastname: Khashab
authors.affiliation: Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center.
authors.forename: Neeraj
authors.initials: N
authors.lastname: Jain
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Jan A
authors.initials: JA
authors.lastname: Burger
authors.affiliation: Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center.
authors.forename: Sattva S
authors.initials: SS
authors.lastname: Neelapu
authors.affiliation: Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center.
authors.forename: R Eric
authors.initials: RE
authors.lastname: Davis
authors.affiliation: Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center fsamaniego@mdanderson.org.
authors.forename: Felipe
authors.initials: F
authors.lastname: Samaniego
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001552:Benzazepines / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015870:Gene Expression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D011379:Prognosis; D011743:Pyrimidines / Q000494:pharmacology*; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D001552:Benzazepines; C000593030:GSK-J4; D011743:Pyrimidines; D011947:Receptors, Antigen, B-Cell; D056484:Jumonji Domain-Containing Histone Demethylases; C524220:KDM6B protein, human