Abstract
Maternal embryonic leucine-zipper kinase (MELK), which was reported to be frequently up-regulated in various types of solid cancer, plays critical roles in formation and maintenance of cancer stem cells. However, little is known about the relevance of this kinase in hematologic malignancies. Here we report characterization of possible roles of MELK in acute myeloid leukemia (AML). MELK is expressed in AML cell lines and AML blasts with higher levels in less differentiated cells. MELK is frequently upregulated in AML with complex karyotypes and is associated with worse clinical outcome. MELK knockdown resulted in growth inhibition and apoptosis of leukemic cells. Hence, we investigated the potent anti-leukemia activity of OTS167, a small molecule MELK kinase inhibitor, in AML, and found that the compound induced cell differentiation and apoptosis as well as decreased migration of AML cells. MELK expression was positively correlated with the expression of FOXM1 as well as its downstream target genes. Furthermore, MELK inhibition resulted in downregulation of FOXM1 activity and the expression of its downstream targets. Taken together, and given that OTS167 is undergoing a phase I clinical trial in solid cancer, our study warrants clinical evaluation of this compound as a novel targeted therapy for AML patients.
Highlights
Maternal embryonic leucine-zipper kinase (MELK) known as MPK38 is a cell-cycle dependent protein kinase that belongs to the AMP-activated Ser/Thr protein kinase family [1, 2]
We found MELK to be expressed at variable levels in different subsets of acute myeloid leukemia (AML) patients
We examined MELK expression in primary blasts obtained from eight patients with AML by quantitative real-time PCR (qRT-PCR), and compared it with that in monocytes obtained from three healthy donors; we found MELK expression to be significantly higher in AML blasts compared to that in monocytes (P = 0.01; Figure 2C)
Summary
MELK (maternal embryonic leucine zipper kinase) known as MPK38 is a cell-cycle dependent protein kinase that belongs to the AMP-activated Ser/Thr protein kinase family [1, 2]. MELK was reported to be expressed in neural progenitors and hematopoietic stem cells [5]. MELK was found to be up-regulated in various types of cancer including breast cancer [3] and glioblastoma [6, 7]. High levels of MELK expression correlated with poorly differentiated histological types of brain tumor and prostate cancer [8,9,10], and is associated with poor prognosis of patients with breast cancer [11]. Several studies have shown that down-regulation of MELK by treatment with siRNA significantly induced apoptosis in breast cancer cells and various types of brain tumor [3, 6]. MELK was identified as one of the genes commonly expressed in undifferentiated cancer cells which may suggest a possible role for MELK in cancer stem cell maintenance and survival [12]
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