Interactome Of Aiolos/Ikaros In Diffuse Large B-Cell Lymphoma (Dlbcl) Reveals Novel Combination Of Cereblon Modulators (Celmod) And Histone Deacetylase (Hdac) Inhibitors

DLBCL is the most common subtype of non-Hodgkin lymphoma, constituting 30-40% of all new cases. Lenalidomide (Len) and Avadomide (Ava), small molecule cereblon modulators (CELMoD) with clinical activity in DLBCL, bind to cereblon in the CRL4CRBN E3 ligase, leading to ubiquitination and subsequent degradation of transcription factors Aiolos and Ikaros. Aiolos/Ikaros bind to the promoters of interferon stimulated genes (ISGs) and repress transcription in DLBCL cells. Degradation of these substrates by Len and Ava results in an upregulation of ISG expression leading to decreased proliferation and increased apoptosis of DLBCL cells. Ava is directly cytotoxic against ABC and GCB-DLBCL cells while Len has preferential activity in ABC-DLBCL. To date, our understanding of the COO independent activity of Ava is due to increased kinetics and greater depth of degradation of Aiolos/Ikaros compared to Len. We sought to further understand the biology of these substrates and their transcriptionally repressive activities in DLBCL.