A novel treatment strategy targeting polo-like kinase 1 in hematological malignancies

Polo-like kinase1 (PLK1) belongs to the family of serine/threonine kinases and plays an important role in centrosome maturation, bipolar spindle formation, and cytokinesis during mitosis. We found in this study that PLK1 was aberrantly highly expressed in a variety of human leukemia cell lines (n = 20), as well as, freshly isolated leukemia cells from individuals with acute myelogenous leukemia (n = 50) and acute lymphoblastic leukemia (n = 15) compared with bone marrow mononuclear cells from healthy volunteers (n = 13) (acute myelogenous leukemia, P = 0.016; acute lymphoblastic leukemia, P = 0.008), as measured by real-time RT-PCR. Downregulation of PLK1 by a small interfering RNA in NB4 acute myelogenous leukemia cells inhibited their proliferation. GW843682X is a novel selective PLK1 inhibitor. The compound-induced growth inhibition, caused accumulation of cells in the G2/M phase of the cell cycle and mediated apoptosis of human leukemia cells. Pre-treatment of cells with the caspase inhibitor Z-VAD-FMK attenuated the action of GW843682X in leukemia cells, indicating the involvement of the caspase pathway in the PLK1 inhibitor-mediated apoptosis. Furthermore, we found that the PLK1 inhibitor synergistically potentiated the growth inhibition and apoptosis of leukemia cells when combined with tubulin-depolymerizing agent vincristine. Taken together, targeting PLK1 may be a promising treatment strategy for individuals with leukemia. Leukemia (2009) 23, 1564-1576; doi: 10.1038/leu.2009.94; published online 7 May 2009