Dissecting the role of aberrant CRL ubiquitin ligases in driving treatment resistance in mantle cell lymphoma and multiple myeloma

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Mantle cell lymphoma (MCL) and multiple myeloma (MM) are incurable mature B-cell malignancies with a median survival of approximately 3-5 years and 5 years, respectively. The poor prognosis typically results from early relapse and the acquisition of resistance towards current targeted treatment modalities which include B-cell receptor targeting agents, proteasome inhibitors (PI) and immunomodulatory drugs (IMiDs), whose anti-tumor activities and resistance mechanisms involve the ubiquitin proteasome system (UPS). Both entities share striking commonalities in terms of treatment response, particularly with regard to PIs and IMiDs. A common investigation thus appears rational and warranted.Our recent studies identified the ubiquitin ligase FBXO25 as a novel tumor suppressor in MCL and specified HAX1 as its substrate, a potent survival protein, which we specify to be involved regulating B-cell receptor signaling as well as sensitivity/resistance of MCL cells towards brutons tyrosine kinase (BTK)-targeting therapies. In a different effort, we identified the ubiquitin ligase KLHL14 as a promising tumor-suppressor in MM and MCL, whose loss represents a MM/MCL-specific dependency. At the same time, treatment with PIs re-establish KLHL14 expression in PI sensitive cells and not in PI resistant cells, suggesting an involvement of KLHL14 in both the molecular mode of action of PIs as well as in resistance to these drugs. Moreover, we unraveled key insights into the molecular mode of action of immunomodulatory drugs (IMiDs), which are central treatment modalities for both MCL and MM. We find these drugs to compete with a fundamental protein quality control and chaperoning function of the ubiquitin ligase CRBN, by which transmembrane proteins of the SLC (solute carrier proteins) family are matured and activated. As a result, these MM cell supporting proteins such as CD147/MCT as well as LAT1/CD98 become destabilized upon IMiD treatment, thereby mediating the anti-tumor activity of IMiDs. By contrast, we show that persistent expression of these CRBN clients mediate IMiD resistance.Based on these studies, we propose to (1) characterize FBXO25 in the context of B cell receptor signaling and acquired resistance towards B-cell receptor targeting therapies (i.e. Ibrutinib) in MCL, to (2) investigate the tumor-suppressor function of KLHL14 in MM and MCL and unravel its role in mediating resistance to proteasome inhibitors and (3) to study the mechanism of IMiD mode of action and resistance in MM and MCL on the basis of CRBNs plasma-membrane-protein specific quality control and chaperoning activity. We anticipate that our multi-disciplinary approach will yield a thorough understanding of how aberrant functions of the ubiquitin machinery drive MCL/MM evolution towards treatment resistance as well as novel therapeutic target structures and biomarkers for the setting of refractory/relapsed MCL/MM.