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Haematologica. 2018 Feb;103(2):325-335. doi: 10.3324/haematol.2017.172973. Epub 2017 Nov 9.

Maternal embryonic leucine zipper kinase is a novel target for proliferation-associated high-risk myeloma.

Author information

1
Wilhelminen Cancer Research Institute, Department of Medicine I, Wilhelminenspital, Vienna, Austria.
2
Laboratory of Hematology, GIGA-I3, University of Liège, Belgium.
3
Center for Medical Statistics, Informatics and Intelligent Systems, Section for Biosimulation and Bioinformatics, Medical University of Vienna, Austria and.
4
Laboratory of Hematology, GIGA-I3, University of Liège, Belgium heinz.ludwig@aon.at jo.caers@chu.ulg.ac.be.
5
Division of Hematology, Department of Medicine, University and CHU of Liège, Belgium.
6
Wilhelminen Cancer Research Institute, Department of Medicine I, Wilhelminenspital, Vienna, Austria heinz.ludwig@aon.at jo.caers@chu.ulg.ac.be.

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.

PMID:
29122991
PMCID:
PMC5792277
DOI:
10.3324/haematol.2017.172973
[Indexed for MEDLINE]
Free PMC Article

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