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Maternal embryonic leucine zipper kinase is a novel target for proliferation-associated high-risk myeloma
Arnold Bolomsky1, Roy Heusschen2, Karin Schlangen3
1Wilhelminen Cancer Research Institute, Department of Medicine I, Wilhelminenspital, Vienna, Austria.
Abstract:
Treatment of high-risk patients is a major challenge in multiple myeloma. This is especially true for patients assigned to the gene expression profiling-defined proliferation subgroup. Although recent efforts have identified some key players of proliferative myeloma, genetic interactions and players that can be targeted with clinically effective drugs have to be identified in order to overcome the poor prognosis of these patients. We therefore examined maternal embryonic leucine zipper kinase (MELK) for its implications in hyper-proliferative myeloma and analyzed the activity of the MELK inhibitor OTSSP167 both in vitro and in vivoMELK was found to be significantly overexpressed in the proliferative subgroup of myeloma. This finding translated into poor overall survival in patients with high vs low MELK expression. Enrichment analysis of upregulated genes in myeloma cells of MELKhigh patients confirmed the strong implications in myeloma cell proliferation. Targeting MELK with OTSSP167 impaired the growth and survival of myeloma cells, thereby affecting central survival factors such as MCL-1 and IRF4 This activity was also observed in the 5TGM.1 murine model of myeloma. OTSSP167 reduced bone marrow infiltration and serum paraprotein levels in a dose-dependent manner. In addition, we revealed a strong link between MELK and other proliferation-associated high-risk genes (PLK-1, EZH2, FOXM1, DEPDC1) and MELK inhibition also impaired the expression of those genes. We therefore conclude that MELK is an essential component of a proliferative gene signature and that pharmacological inhibition of MELK represents an attractive novel approach to overcome the poor prognosis of high-risk patients with a proliferative expression pattern.
Insights
Maternal embryonic leucine kinase (MELK) is overexpressed in high-risk multiple myeloma, correlating with poor survival. Inhibiting MELK with OTSSP167 reduced cancer growth and survival, offering a potential new treatment strategy.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- High-risk multiple myeloma presents treatment challenges, particularly in the gene expression profiling-defined proliferation subgroup.
- Identifying novel therapeutic targets is crucial for improving outcomes in proliferative myeloma patients.
- Maternal embryonic leucine zipper kinase (MELK) has been implicated in cancer proliferation but requires further investigation in myeloma.
Purpose of the Study:
- To investigate the role of MELK in hyper-proliferative multiple myeloma.
- To evaluate the efficacy of the MELK inhibitor OTSSP167 in vitro and in vivo.
- To explore the relationship between MELK and other high-risk proliferation genes.
Main Methods:
- Gene expression analysis to assess MELK levels in myeloma patient subgroups.
- In vitro studies using myeloma cell lines to evaluate OTSSP167's effect on cell growth and survival.
- In vivo studies using the 5TGM.1 murine myeloma model to assess OTSSP167's therapeutic potential.
Main Results:
- MELK was significantly overexpressed in the proliferative subgroup of myeloma, associated with poorer overall survival.
- OTSSP167 treatment inhibited myeloma cell growth and survival by affecting key factors like MCL-1 and IRF4.
- In vivo, OTSSP167 dose-dependently reduced bone marrow infiltration and paraprotein levels in a murine model.
- MELK inhibition also decreased the expression of other proliferation-associated genes, including PLK-1, EZH2, FOXM1, and DEPDC1.
Conclusions:
- MELK is a critical component of the proliferative gene signature in multiple myeloma.
- Pharmacological inhibition of MELK using OTSSP167 demonstrates promising therapeutic potential.
- Targeting MELK offers a novel strategy to improve outcomes for high-risk patients with a proliferative myeloma subtype.
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