The homeobox transcription factor MEIS2 is a regulator of cancer cell survival and IMiDs activity in Multiple Myeloma: modulation by Bromodomain and Extra-Terminal (BET) protein inhibitors

Abstract

The transcription factor Myeloid Ecotropic Insertion Site 2 (MEIS2) has been identified as a cellular substrate of the E3-ubiquitin ligase complex CRL4-cereblon ( CRL4 CRBN) 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 CRL4 CRBN 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.

Immunomodulatory effect of NEDD8-activating enzyme inhibition in Multiple Myeloma: upregulation of NKG2D ligands and sensitization to Natural Killer cell recognition

“…6D–F ), configuring MLN4924 as a modulator of the NF-kB/IRF4/MICA axis. Moreover, we also analyzed the expression of IKZF3 and IKZF1, two TFs required for MM growth and survival [ 46 ], which are known to negatively control the functional properties of many immune cells [ 46 ], and to repress MICA gene expression in MM [ 35 , 47 ]. As shown in Supplementary Fig.…”

Prognostic Significance of Cyclin E1 Expression in Patients With Chordoma: A Clinicopathological and Immunohistochemical Study

“…In terms of frequency, the cyclin E1 gene is one of the most commonly amplified genes in ovarian cancer (19%), anaplastic thyroid cancer (29%) and osteosarcoma (27-33%) ( 14 , 17 , 18 , 29 ). Overexpression of transcription factors such as c-MYC and MEIS2 directly up-regulate cyclin E1 expression ( 30 , 31 ). In addition, inactivation of core units central to the ubiquitin protein ligase complex lead to cyclin E1 overexpression, as this is its principal degradative mechanism ( 32 ).…”

Epigenetic silencing of MEIS2 in prostate cancer recurrence

“…Although epigenetic silencing of MEIS2 has also been described in lung and hepatocellular carcinoma cell lines as well as colorectal cancer [39–41], the function of MEIS2 in other cancers remains unclear and may be highly disease-specific as MEIS2 is downregulated in some cancers and upregulated in others [13]. In neuroblastoma, leukemia, and multiple myeloma, MEIS2 serves as an oncogene [42–45] and, similarly seems to play an important role in tumor cell migration and invasion in bladder and colorectal cancer [46, 47]. MEIS2 expression may also be involved in chemotherapy sensitivity, although current results are conflicting.…”

“…MEIS2 expression may also be involved in chemotherapy sensitivity, although current results are conflicting. Thus, MEIS2 knockdown increases responsiveness to chemotherapy in multiple myeloma, whereas MEIS2 is downregulated in colorectal cancer patients resistant towards oxaliplatin-based chemotherapy [41, 45]. Contradictory results also exist regarding prognosis.…”