Reference : Maternal embryonic leucine zipper kinase is a novel target for proliferation associat...
Scientific journals : Article
Human health sciences : Hematology
http://hdl.handle.net/2268/220924
Maternal embryonic leucine zipper kinase is a novel target for proliferation associated high-risk myeloma.
English
Bolomsky, Arnold [> >]
Heusschen, Roy mailto [Université de Liège - ULiège > > GIGA-R : Hématologie >]
Schlangen, Karin [> >]
Stangelberger, Kathrin [> >]
Muller, Joséphine mailto [Université de Liège - ULiège > > GIGA-R : Hématologie >]
Schreiner, Wolfgang [> >]
Zojer, Niklas [> >]
Caers, Jo mailto [Université de Liège - ULiège > Département des sciences cliniques > Département des sciences cliniques >]
Ludwig, Heinz [> >]
2017
Haematologica
Yes (verified by ORBi)
International
0390-6078
1592-8721
Italy
[en] MELK ; Multiple Myeloma ; OTSSP167 ; high-risk ; proliferation
[en] 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 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 analysed the activity of the MELK inhibitor OTSSP167 in vitro and in vivo. MELK 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 of 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.
http://hdl.handle.net/2268/220924
10.3324/haematol.2017.172973
Copyright (c) 2017, Ferrata Storti Foundation.

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