Maternal embryonic leucine zipper kinase is a novel target for diffuse large B cell lymphoma and mantle cell lymphoma.
Anke MaesKen MaesPhilip VlummensHendrik De RaeveJulie DevinVanessa SzablewskiKim De VeirmanEline MenuJérôme MoreauxKarin VanderkerkenElke De BruynePublished in: Blood cancer journal (2019)
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.
Keyphrases
- diffuse large b cell lymphoma
- cell cycle
- epstein barr virus
- poor prognosis
- induced apoptosis
- small molecule
- cell cycle arrest
- cancer therapy
- cell proliferation
- long non coding rna
- cell death
- high glucose
- diabetic rats
- endoplasmic reticulum stress
- oxidative stress
- tyrosine kinase
- drug delivery
- squamous cell carcinoma
- protein protein
- signaling pathway
- case report
- adipose tissue
- transcription factor
- single cell
- body mass index
- drug induced
- papillary thyroid
- pi k akt
- squamous cell
- stress induced
- climate change
- skeletal muscle
- human health
- weight gain