Abstract LB-376: Deregulation of promoter methylation of the polo-like kinases in myelodysplastic syndromes (MDS) and other blood neoplasms
Authors: Alejandra Ward, Gayathri Sivakumar, Caroline Hamm, Sindu Kanjeekal, John W. Hudson
Journal: Cancer Research (2012)

Abstract The polo-like kinases (Plks) are a cell cycle regulated family of proteins which are critical for several important cell cycle events which include entry into M-phase, cytokinesis, centriole duplication, and the DNA damage response. Deregulation of individual Plks have been associated with a malignant state. Typically, Plk1 has oncogenic properties and has been shown to be over-expressed in several types of malignancies such as head and neck squamous carcinomas and hepatocellular carcinoma. In the latter case, we previously demonstrated that in some cases this is due to loss of methylation in its promoter region with a corresponding change in expression. In contrast, we and others, have determined that plk2, plk4, and plk5 are often downregulated through DNA hypermethylation in blood neoplasms, hepatocelluar carcinoma, and glioblastoma, respectively. More specifically, plk2 is often hypermethylated at its promoter region in B-cell lymphomas, myelodysplastic syndromes (MDS) and acute myeloid leukemia. However, these studies have not been expanded to include the other plks. The purpose of the present study was to determine the methylation status of plks 1-5 in MDS and MDS derived blood neoplasms. Interestingly, we have determined that the plk1 promoter is methylated in 100% of normal bone marrow biopsies, whereas, in a malignant state, the methylation is found in only 60% of lymphomas and approximately 64% of MDS and leukemia samples assayed. Moreover, we see the opposite scenario occurring in the plk4 promoter region; in the normal samples, there was detectable promoter methylation in only 20% of our samples. Inversely, 80% of lymphoma and 64% of MDS and leukemia bone marrow samples were positive for methylation. A similar scenario was observed for plk3 in lymphoma bone marrow samples. The promoter methylation pattern noted above also corresponds to the pattern observed in a number of established cell lines derived from MDS patients with the exception of plk1, which is methylated in a subset of the lines tested. We have also initiated an analysis on the effect of common treatment regimes for MDS, such as Decitabine (5-aza-2′-deoxycytidine), on the methylation status of the plks in these cell lines. In the case of cells exposed to decitabine for a period of 7 days, we observed a decrease in the promoter methylation status for both plk1 and plk3. This indicates that the plks become deregulated in vivo through epigenetic mechanisms in blood neoplasms and are susceptible to demethylating agents in vitro. Given their critical roles in DNA damage and cell division, this aberrancy may contribute to tumourigenicity in MDS patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-376. doi:1538-7445.AM2012-LB-376