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.
The mechanisms by which bromodomain and extra-terminal domain (BET) protein inhibitor I-BET151 regulates osteoclast differentiation and inflammatory cytokine secretion in MM are largely unknown.
We explored the transcriptional and functional interrelationship between E2F transcription factors and BET transcriptional co-activators in multiple myeloma.
Our studies further underscored that the BET inhibitor OTX015 sensitized MM cells by interrupting several pathways and genes critical for MM cell proliferation and drug response, which provided the rationale for multiple myeloma therapy with OTX015 combined with conventional chemotherapeutic drugs.
The BET bromodomain inhibitor CPI203 improves lenalidomide and dexamethasone activity in <i>in vitro</i> and <i>in vivo</i> models of multiple myeloma by blockade of Ikaros and MYC signaling.
We found that treatment of human multiple myeloma (MM) cells with the small-molecular inhibitor of BET bromodomains, (+)-JQ1, selectively downregulated <i>MYC</i> transcription, which is similar to what was reported in the original study (Figure 3B; Delmore et al., 2011).
Collectively, these data qualify BMI-1 as a candidate for targeted therapy in MM alone or in combinations with epigenetic inhibitors directed to PRC2/EZH2 or BET bromodomains.
Efficacy of JQ1 in three murine models of multiple myeloma establishes the therapeutic rationale for BET bromodomain inhibition in this disease and other malignancies characterized by pathologic activation of c-Myc.