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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • Humans
  • Mice
  • Multiple Myeloma / drug therapy*
  • Multiple Myeloma / pathology
  • Naphthyridines / pharmacology
  • Prognosis
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Serine-Threonine Kinases / metabolism
  • Risk Assessment

Substances

  • 1-(6-(3,5-dichloro-4-hydroxyphenyl)-4-((4-((dimethylamino)methyl)cyclohexyl)amino)-1,5-naphthyridin-3-yl)ethanone
  • Naphthyridines
  • MELK protein, human
  • Protein-Serine-Threonine Kinases