Abstract
Currently considered incurable, multiple myeloma (MM) is characterized by proliferation of malignant plasma cells (PC) predominantly in the bone marrow, which overproduce monoclonal immunoglobulin proteins, and a perturbed tumor microenvironment, which promotes PC survival, inhibits osteoblast activity, increases osteoclast activity, and leads to hallmark osteolytic bone disease, all of which contribute to the clinical manifestations of the disease. Disrupting these sequelae by incorporation of proteasome inhibitors and immunomodulatory drugs into treatment regimens has improved overall survival of MM patients; however, the majority of patients will become refractory to the most effective currently available therapeutic options and relapse.1 It is hypothesized that a drug-resistant population of myeloma stem cells promotes disease relapse, but the characteristics and identity of this cell type(s) remain uncertain.2 Expression of maternal embryonic leucine zipper kinase (MELK) is increased in a number of cancers and is associated with poorer prognosis. MELK activity modulates many cellular and biological processes, including proliferation, apoptosis, hematopoiesis and oncogenesis, and is believed to have a critical role in cancer stem cell maintenance.3
Highlights
Considered incurable, multiple myeloma (MM) is characterized by proliferation of malignant plasma cells (PC) predominantly in the bone marrow, which overproduce monoclonal immunoglobulin proteins, and a perturbed tumor microenvironment, which promotes PC survival, inhibits osteoblast activity, increases osteoclast activity, and leads to hallmark osteolytic bone disease, all of which contribute to the clinical manifestations of the disease
We assessed the expression of maternal embryonic leucine zipper kinase (MELK) mRNA in malignant PC derived from MM patients and human myeloma cell lines (HMCL) and effects of the MELK inhibitor OTS167 on myeloma cells, including drug-resistant subclones
MELK gene expression analysis was performed on publically available data sets GSE5900,4 GSE2658 and GSE6477 and demonstrated significantly increased MELK mRNA expression in newly diagnosed MM PC (n = 628) compared with either normal PC, monoclonal gammopathy of undetermined significance (MGUS) CD138+ PC (n = 65; Po0.0001), or PC from smoldering MM patients (n = 36; P = 0.0003; Figure 1a)
Summary
Anti-myeloma activity of MELK inhibitor OTS167: effects on drug-resistant myeloma cells and putative myeloma stem cell replenishment of malignant plasma cells. Myeloma survival factors c-Myc and IRF4 decreased in a dose-dependent manner in both cell lines.[12] p53 levels decreased in U266 cells but were only modestly changed in MM1S cells, and the p53 target, p21, was increased in p53 wild-type cells and fluctuated in p53 mutant cells, which agreed with previous findings.[14] Altogether, these data reveal potent apoptotic effects of OTS167 in malignant MM PC, support the potential for OTS167 to overcome drug resistance, and define novel targets of MELK whose inhibition is known to promote myeloma cell death.
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