Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UMLS:C0026764 (
multiple myeloma
)
36,148
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
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 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
MELK
high
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:Maternal embryonic leucine zipper kinase is a novel target for proliferation-associated high-risk myeloma. 2912 91
