1. Academic Validation
  2. Maternal embryonic leucine zipper kinase is a novel target for diffuse large B cell lymphoma and mantle cell lymphoma

Maternal embryonic leucine zipper kinase is a novel target for diffuse large B cell lymphoma and mantle cell lymphoma

  • Blood Cancer J. 2019 Nov 18;9(12):87. doi: 10.1038/s41408-019-0249-x.
Anke Maes 1 Ken Maes 1 Philip Vlummens 1 2 Hendrik De Raeve 3 Julie Devin 4 Vanessa Szablewski 5 Kim De Veirman 1 Eline Menu 1 Jerome Moreaux 4 Karin Vanderkerken 1 Elke De Bruyne 6
Affiliations

Affiliations

  • 1 Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium.
  • 2 Hematology, Department of Internal Medicine, Ghent University Hospital, Ghent, Belgium.
  • 3 Department of Pathology, UZ Brussel, Vrije Universiteit Brussel, Brussels, Belgium.
  • 4 Laboratory for Monitoring Innovative Therapies, Institute of Human Genetics, CNRS, Montpellier, France.
  • 5 Department of Biopathology, CHU Montpellier, France.
  • 6 Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium. Elke.De.Bruyne@vub.be.
Abstract

Diffuse large B cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) are among the most aggressive B cell non-Hodgkin lymphomas. Maternal embryonic leucine zipper kinase (MELK) plays a role in Cancer cell cycle progression and is associated with poor prognosis in several Cancer cell types. In this study, the role of MELK in DLBCL and MCL and the therapeutic potential of MELK targeting is evaluated. MELK is highly expressed in DLBCL and MCL patient samples, correlating with a worse clinical outcome in DLBCL. Targeting MELK, using the small molecule OTSSP167, impaired cell growth and survival and induced caspase-mediated Apoptosis in the lymphoma cells. Western blot analysis revealed that MELK targeting decreased the phosphorylation of FOXM1 and the protein levels of EZH2 and several mitotic regulators, such as Cdc25B, cyclin B1, Plk-1, and Aurora kinases. In addition, OTSSP167 also sensitized the lymphoma cells to the clinically relevant Bcl-2 Inhibitor venetoclax by strongly reducing Mcl1 levels. Finally, OTSSP167 treatment of A20-inoculated mice resulted in a significant prolonged survival. In conclusion, targeting MELK with OTSSP167 induced strong anti-lymphoma activity both in vitro and in vivo. These findings suggest that MELK could be a potential new target in these aggressive B cell malignancies.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-15512
    99.70%, MELK 抑制剂