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

套细胞淋巴瘤（MCL）和多发性骨髓瘤（MM）是无法治愈的成熟b细胞恶性肿瘤，中位生存期分别约为3-5年和5年。不良预后通常是由于早期复发和对当前靶向治疗方式的耐药性，包括b细胞受体靶向药物，蛋白酶体抑制剂（PI）和免疫调节药物（IMiDs），其抗肿瘤活性和耐药机制涉及泛素蛋白酶体系统（UPS）。这两个实体在治疗反应方面有着惊人的共同点，特别是在药物抑制剂和免疫缺陷药物方面。因此，一项共同的调查似乎是合理和必要的。我们最近的研究发现泛素连接酶FBXO25是MCL中的一种新的肿瘤抑制因子，并指定HAX1作为其底物，这是一种有效的生存蛋白，我们指定它参与调节b细胞受体信号传导以及MCL细胞对brutons酪氨酸激酶（BTK）靶向治疗的敏感性/耐药性。在另一项研究中，我们发现泛素连接酶KLHL14在MM和MCL中是一种很有前景的肿瘤抑制因子，其缺失代表了MM/MCL特异性依赖性。与此同时，用PI治疗后，KLHL14在PI敏感细胞中重新表达，而在PI耐药细胞中没有表达，这表明KLHL14既参与PI的分子作用方式，也参与对这些药物的耐药性。此外，我们揭示了免疫调节药物（IMiDs）的分子作用模式的关键见解，这些药物是MCL和MM的核心治疗方式。我们发现这些药物与泛素连接酶CRBN的基本蛋白质质量控制和陪伴功能竞争，通过该功能，SLC（溶质载体蛋白）家族的跨膜蛋白成熟和激活。因此，这些MM细胞支持蛋白如CD147/MCT和LAT1/CD98在IMiD治疗后变得不稳定，从而介导IMiD的抗肿瘤活性。相比之下，我们发现这些CRBN客户端的持续表达介导了IMiD抗性。基于这些研究，我们提出(1)在B细胞受体信号传导和MCL中对B细胞受体靶向治疗（如伊鲁替尼）获得性耐药的背景下表征FBXO25；(2)研究KLHL14在MM和MCL中的抑瘤功能，揭示其在介导蛋白酶体抑制剂耐药中的作用；(3)基于crbn质膜蛋白特异性质量控制和伴随活性，研究IMiD在MM和MCL中的作用方式和耐药机制。我们预计，我们的多学科方法将全面了解泛素机制的异常功能如何驱动MCL/MM向治疗耐药性发展，以及难治性/复发性MCL/MM的新治疗靶点结构和生物标志物。

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.