Genetic Alterations Affecting Ubiquitination in Multiple Myeloma
Ubiquitination plays a key role in the pathophysiology of multiple myeloma, highlighting its promise as a therapeutic target for this plasma cell malignancy. In this blog, we used Causaly to explore genetic alterations affecting by ubiquitination in multiple myeloma.
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Overview
Ubiquitination plays a key role in the pathophysiology of multiple myeloma, highlighting its promise as a therapeutic target for this plasma cell malignancy. In this blog, we used Causaly to explore genetic alterations affecting by ubiquitination in multiple myeloma.
Introduction
Multiple myeloma, a blood cancer causing plasma cell overgrowth in the bone marrow, is becoming increasingly prevalent worldwide, particularly in the U.S., Australia, and Western Europe.¹ In 2021, approximately 35,000 individuals in the U.S. were diagnosed with myeloma, with an estimated mortality rate of around 36%.²
Identifying novel therapeutic targets and understanding the molecular drivers of disease are key in advancing cancer treatments. A prime example is the FDA’s recent accelerated approval of talquetamab-tgvs for relapsed and pre-treated multiple myeloma patients.³ This antibody targets GPRC5D, a protein overexpressed in multiple myeloma, highlighting the promise of targeted immunotherapy. Intriguingly, many immunomodulating drugs enhance ubiquitination – a process dysregulated in multiple myeloma.⁴ In this blog, we delve into genetic alterations affecting ubiquitination in this disease.
Ubiquitination: A Fundamental Cellular Process
Ubiquitination, mediated by the ubiquitin-proteasome system, regulates protein degradation and function, impacting proteins including cell cycle regulators, transcription factors and immune system proteins. When this system malfunctions, it can spur cancer development by causing protein accumulation, genetic instability, and unregulated cell growth signals. Such disruptions in ubiquitination can influence the behavior of tumor suppressor genes and oncogenes, which are pivotal in cancer progression.⁵ In the context of multiple myeloma, aberrant ubiquitination may play a significant role.
Ubiquitination in Multiple Myeloma
Using Causaly, around 50 genetic alterations affecting ubiquitination in multiple myeloma were uncovered. Two recently reported mutated genes affecting ubiquitination in the context of multiple myeloma were RNF6 and HERC4. Both genes encode for ubiquitin ligases – proteins essential in the ubiquitination process.
- Ring Finger Protein 6 (RNF6): RNF6 is a protein which has shown to promote tumorigenesis in various cancers via ubiquitination, protein degradation and transcriptional regulation.⁶ Recent studies have shed light on RNF6's involvement in multiple myeloma. A study showed that RNF6 undergoes auto-ubiquitination, which can be abolished by the deubiquitinase USP7.⁷ As such, the potential for inducing RNF6 auto-ubiquitination and degradation could be a novel therapeutic strategy for treating hematological malignancies, including multiple myeloma and leukemia.
- HECT and RLD domain-containing E3 ubiquitin ligase 4 (HERC4): In multiple myeloma , HERC4, a regulatory ubiquitin ligase implicated in various malignancies, exhibits an inverse correlation with disease progression, suggesting a tumor-suppressive role.⁸ A 2023 study reported that HERC4 plays a role in suppressing the activity of MafA in multiple myeloma.⁸ Lithium chloride was shown to enhance HERC4 activity, and when combined with the common treatment drug dexamethasone, it reduced cancer cell growth.⁸
Conclusion
Understanding the role of ubiquitination in multiple myeloma presents a promising avenue for refining treatment strategies. Interactions with the ubiquitin-proteasome system might influence the survival of myeloma cells, potentially impacting treatment outcomes. As research continues, the relationship between ubiquitination and multiple myeloma could influence emerging treatment considerations, offering a glimpse of hope for those affected by this disease.
References
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- Siegel, R., Miller, K. D., Fuchs, H. E., et. al., CA: Cancer J. Clin., 2021;71(1):7-33. Source
- FDA.gov Source
- Cao, B., Mao, X., Am. J. Blood. Res., 2011;1(1):46-56. Source
- Kitagawa, K., Kotake, Y., Kitagawa, M., Cancer Sci., 2009;100(8):1374-81. Source
- Xu, H., Wong, C. C., Li, W. et al., Oncogene, 2021;40(1):6513–6526. Source
- Zhuang, H., Ren, Y., Mao, C., et. al., J. Biol. Chem., 2022;298(9):102314. Source
- Zhang, Z., Li, M., Lin, P., et. al., J. Biol. Chem., 2023;299(5):104675. Source
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