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 (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 CRL4CRBNIMiD-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.
Highlights
Myeloid Ecotropic Insertion Site 2 (MEIS2) is a homeobox transcription factor (TF) member of the Three Amino-acid Loop Extension (TALE) family of homeo-domain-containing transcription factors, important regulators of cell proliferation during development and involved in skeletal muscle differentiation, development of hindbrain and proximal-distal limb patterning[1,2,3,4]
In this study, we investigated on the role of the transcription factor MEIS2 in MM, the activity of BET inhibitors (BETi) or PROTAC-mediated Inhibition/degradation of Bromodomain and Extra-Terminal (BET) proteins on its expression, and the functional implications of its modulation on the activity of selected chemotherapics, focusing on IMiDs
A similar modality of cell death was previously described in MM cells after IRF4 knockdown, a critical transcription factor regulator, together MYC, of many genes involved in cell survival/ apoptosis in MM40 and downregulated by MEIS2 small-hairpin RNAs (shRNAs) interference (Fig. 5f–h)
Summary
MEIS2 is a homeobox transcription factor (TF) member of the Three Amino-acid Loop Extension (TALE) family of homeo-domain-containing transcription factors, important regulators of cell proliferation during development and involved in skeletal muscle differentiation, development of hindbrain and proximal-distal limb patterning[1,2,3,4]. Abruzzese et al Cell Death and Disease (2019)10:324 an oncogenic role for MEIS TFs in the growth and progression of human cancers. MEIS2 affects neuroblastoma proliferation and differentiation, playing a critical role in the control of late cell-cycle genes[8,9]. Tumor expression of MEIS2 confers a more indolent prostate cancer phenotype, with a decreased propensity for metastatic progression, suggesting cancer specific mechanisms[10]. MEIS2 has been identified as a novel player in Meningioma-1 (MN1)-induced leukemogenesis[11] and its expression is essential for maintaining myeloid cell lines in an undifferentiated-proliferating state by inhibiting myeloid differentiation[12]
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