Abstract
B-cell acute lymphoblastic leukemia (B-ALL) accounts for nearly one fifth of all childhood cancers and current challenges in B-ALL treatment include resistance, relapse and late-onset side effects due to the chemotherapy. To overcome these hurdles, novel therapies need to be investigated. One promising target is Polo-like kinase 1 (Plk1), a key regulator of the cell cycle. In this study, the Plk family expression is investigated in primary peripheral blood and bone marrow mononuclear cells from ten pediatric B-ALL patients. For the first time, short interfering RiboNucleic Neutrals (siRNNs) that enter cells without a transfection reagent are used to target Plk1 mRNA in primary cells from pediatric B-ALL patients. Our results show that the expression of Plk1 and Plk4 is significantly higher in pediatric B-ALL patients compared to healthy donors. Moreover, treatment of primary peripheral blood and bone marrow mononuclear cells from pediatric B-ALL patients, cultured ex vivo, with Plk1-targeting siRNNs results in cleavage of Plk1 mRNA. Importantly, the Plk1 knockdown is specific and does not affect other Plk members in contrast to many small molecule Plk1 inhibitors. Thus, Plk1 is a potential therapeutic target in pediatric B-ALL and selective targeting of Plk1 can be achieved by the use of siRNNs.
Highlights
B-cell acute lymphoblastic leukemia (B-ALL) accounts for nearly one fifth of all childhood cancers and current challenges in B-ALL treatment include resistance, relapse and late-onset side effects due to the chemotherapy
We investigated if short interfering RiboNucleic Neutrals (siRNNs) targeting Polo-like kinase family (Plk)[1] were able to enter B-ALL cell lines and induce specific mRNA knockdown followed by cell cycle arrest and apoptosis
The analysis showed that the expression pattern of Plks between the B-ALL cells and normal B-cells followed the same trend that we observed using our samples in regard to Plk[1] (Supplementary Fig. 8A) and Plk[4] (Supplementary Fig. 8D) mRNA expression, as they were significantly higher in B-ALL samples compared to sorted B-cells
Summary
B-cell acute lymphoblastic leukemia (B-ALL) accounts for nearly one fifth of all childhood cancers and current challenges in B-ALL treatment include resistance, relapse and late-onset side effects due to the chemotherapy To overcome these hurdles, novel therapies need to be investigated. The most well-studied member, Polo-like kinase 1 (Plk1), has a number of distinct roles in cell cycle regulation such as G2/M transition, mitotic spindle assembly and cytokinesis that all promote cell cycle progression[6,7,8] Due to these functions, Plk[1] expression is high in actively dividing tissues and often overexpressed both in solid tumor and hematologic malignancies[9,10,11,12]. Full-length blots and quantification of blots can be found in Supplementary Figs. 1 and 2, respectively
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