Multiple myeloma, a malignancy of plasma cells, is the second most common hematological cancer. Despite major advances in therapy with the use of bortezomib, thalidomide, and lenalidomide (immunomodulatory inhibitory drugs (IMiDs)), which impact favorable prognosis and survival, multiple myeloma still remains incurable. Therefore, further understanding of the transforming mechanisms to allow for the development of new therapeutics is needed. A small set of transcription factors (TFs) has been found to play a critical role in cell regulatory networks and pathogenesis of multiple myeloma. The protein abundance of these key TFs is regulated at multiple levels, influencing transcriptional rates. However, data are also emerging on mechanisms of transcription- and translation-independent regulation. For instance, viruses have been shown to specifically subvert certain ubiquitin ligases to modulate TF abundance, by regulating TF poly-ubiquitination and as such influencing proteasome-mediated TF degradation. Recent mechanism-of-action studies showed that IMiDs redirect Ikaros TFs toward the E3 ligase Cullin4-CRBN for ubiquitination and degradation via the proteasome.
Our laboratories are interested in developing cellular systems that enable genetic and low-molecular weight compound screening of regulators of TF abundance by multiplexing readouts of transcriptional and degradation rates. With this approach, we aim to elucidate the underlying biology of TF regulatory networks in MM pathology and B-cell development, with a focus on mechanisms regulating TF protein stability. To this end, we are combining state-of-the-art genetic tools including CRISPR, deep-coverage shRNA pools and live-cell fluorescent sensors, as well as single-cell analysis combined with next-generation sequencing approaches.