3050 – REIIBP PROMOTES TLR7-BTK-IL6 PRO-INFLAMMATORY RESPONSE THROUGH HISTONE H3 LYSINE METHYLATION IN T(4;14) MYELOMAGENESIS

REIIBP is a t(4;14)-deregulated histone methyltransferase arising from alternative promoter usage within the MMSET locus. Despite sharing identical sequence with C-terminus of MMSET, we found that displayed distinct expression pattern other breakpoint variants and gene products t(4;14) Additionally, can be regulated through microRNAs by another methyltransferase, EZH2 in Dicer-dependent manner. Stable overexpression t(4;14)-negative RPMI8226 promoted oncogenic phenotypes predominantly catalyzes repressive H3K27me3 active H3K4me3 modifications. Identification differentially-regulated genes microarray correlation H3K4me3/H3K27me3 ChIP-sequencing revealed Toll-like receptor 7 (TLR7) Bruton's tyrosine kinase (BTK) are targets REIIBP. Importantly, this led to B-cell (BCR)-independent activation BTK NF-κB effector signaling myeloma cells. As cells do not express BCR, re-activation TLR7 was functionally validated, conferring bortezomib resistance dysregulation pro-inflammatory cytokine such as IL-6 IL-27. Furthermore, comparison dependency scores across lineages an important target multiple myeloma, correlated CoMMpass dataset. t(4;14)-translocated were amenable targeting using Ibrutinib, improving response mice engrafted RPMI8226-REIIBP tumors. Altogether, our results provided rationale for blockade combining proteasome inhibitors therapeutic strategy further clinical evaluation.