AbstractThe transcription factor Myeloid Ecotropic Insertion Site 2 (MEIS2) has been identified as a cellular substrate of the E3-ubiquitin ligase complex CRL4-cereblon (^CRL4CRBN) in crystal structure and by biochemical screen. Emerging evidence suggests that IMiDs can block MEIS2 from binding to CRBN facilitating the subsequent activation of a ^CRL4CRBN^IMiD-E3-ubiquitin ligase activity and proteasome-mediated degradation of critical substrates regulators of Multiple Myeloma (MM) cell survival and proliferation. Bromodomain and Extra-Terminal (BET) family of proteins are important epigenetic regulators involved in promoting gene expression of several oncogenes, and many studies have revealed important anticancer activities mediated by BET inhibitors (BETi) in hematologic malignancies including MM. Here, we investigated MEIS2 in MM, the role of this protein as a modulator of IMiDs activity and the ability of BETi to inhibit its expression. Our observations indicate that inhibition of MEIS2 in MM cells by RNA interference correlates with reduced growth, induction of apoptosis and enhanced efficacy of different anti-MM drugs. In addition, MEIS2 regulates the expression of Cyclin E/CCNE1 in MM and induction of apoptosis after treatment with the CDK inhibitor Seliciclib/Roscovitine. Interestingly, modulation of MEIS2 can regulate the expression of NKG2D and DNAM-1 NK cell-activating ligands and, importantly, the activity of IMiDs in MM cells. Finally, BETi have the ability to inhibit the expression of MEIS2 in MM, underscoring a novel anticancer activity mediated by these drugs. Our study provides evidence on the role of MEIS2 in MM cell survival and suggests therapeutic strategies targeting of MEIS2 to enhance IMiDs anti-myeloma activity.