NF-ΚB ACETYLATION AS A POSSIBLE MECHANISM OF RESISTANCE TO HISTONE DEACETYLASE INHIBITORS IN DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL)

picture of Samantha Doctor presenting his/her poster: NF-ΚB ACETYLATION AS A POSSIBLE MECHANISM OF RESISTANCE TO HISTONE DEACETYLASE INHIBITORS IN DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL)

Samantha Doctor , Tula-Sanchez A, Smith CL

NF-ΚB ACETYLATION AS A POSSIBLE MECHANISM OF RESISTANCE TO HISTONE DEACETYLASE INHIBITORS IN DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL)

Diffuse Large B-cell Lymphoma (DLBCL) is a common and aggressive form of Non-Hodgkin Lymphoma (NHL). About 30% of DLBCL patients undergo early relapse or do not respond at all to current chemotherapeutic approaches. DLBCL has two cell-of-origin forms; the activated B cell (ABC) subtype and the germinal center (GCB) subtype. The ABC subtype is the least curable form of this disease. It is in this subtype that the protein NF-κB is constitutively active. NF-κB is a transcription factor that is involved in inflammatory processes, promotes cell proliferation, and protects the cell from apoptosis. The anti-apoptotic effects of NF-κB are attributed to its capability to induce transcription of the anti-apoptotic protein Bcl-2. Histone deacetylase inhibitors (HDACi) are a class of anti-cancer drugs that have shown promising results in combating hematological malignancies such as DLBCL. However, it has been recently demonstrated that some DLBCL cell lines are resistant to cell death by HDACi treatment. Acetylation of NF-κB is known to increase its transcriptional activity. Because HDAC inhibition causes general increases in protein acetylation, we hypothesize that increased NF-κB acetylation and consequent activation might contribute to HDACi resistance in DLBCL through its anti-apoptotic effects. To address our hypothesis we will determine whether the pan-HDACi, PXD101, alters NF-κB acetylation, interaction with its inhibitor IkB, translocation to the nucleus, or binding to DNA in DLBCL cell lines that are sensitive or resistant to HDACi. We have already determined that NF-κB activity is increased by PXD101 treatment in one of the resistant cell lines. We have also shown that PXD101 does not cause translocation of NF-κB to the nucleus, suggesting that HDACi treatment does not result in decreased interaction with IkB. Ongoing studies are directed at immunoprecipitation of NF-κB to measure its acetylation and association with IkB.  In addition, we will measure PXD101-induced changes in NF-κB DNA binding and transcriptional activity through pulldown and reporter gene assays.

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