Figure 5 from p97 Inhibition Synergistically Enhances Hypomethylating Therapy through Targeting of PLK1 in Acute Myeloid Leukemia
Year: 2026
Type: other
Abstract: PLK1 is a key pharmacodynamic target of the CB-5339/DAC combination. A, Targeted PLK1 knockdown impairs AML cell proliferation. MOLM-13 cells were transduced with nontargeted control of PLK1-targeted lentiviral shRNA. Knockdown efficiency was determined by immunoblotting. Cell numbers were quantified for both conditions at 48 hours after lentiviral transduction. N = 3 ± SD; * indicates a significant difference from control shRNA, P < 0.005. B and C, Effects of targeted PLK1 knockdown on sensitivity to CB-5339 and DAC. MOLM-13 cells were infected with lentiviral nontargeted control or PLK1-targeted shRNA. Cells were treated with the indicated concentrations of CB-5339 and DAC. Cell viability was determined by MTT assay. N = 3 ± SD; * indicates a significant difference from control shRNA, P < 0.05. D, High PLK1 expression is associated with resistance to hypomethylating therapy. Within the ELN2022 adverse-risk group, patients with AML were stratified based on PLK1 levels comparing PLK1-low expression (bottom 25%) and PLK1-high expression (top 25%). Hypomethylating therapy response (azacitidine) is shown as an AUC in which higher values indicate greater resistance. Each dot represents an individual patient. Statistical significance was determined using a two-sided Wilcoxon rank-sum test (*, P = 0.05). E, PLK1 is a determinant of sensitivity to the CB-5339/DAC combination. MOLM-13 cells transduced with nontargeted control shRNA or PLK1-targeted shRNA lentiviral vectors were treated with 250 nmol/L CB-5339, 500 nmol/L DAC, or both drugs for 72 hours. The impact of drug treatment on cell viability was determined by MTT assay. N = 3 ± SD; * indicates a significant difference from control shRNA, P < 0.005. F, Overexpression of PLK1 promotes resistance to CB-5339 and DAC. PLK1 was overexpressed in MOLM-13 cells using PLK1-Myc-DDK lentiviral particles. Overexpression efficiency was assessed by immunoblotting. Vector control and PLK1-overexpressing cells were treated with 200 nmol/L CB-5339, 300 nmol/L DAC, and the combination for 72 hours. The effects of drug treatment on cell viability were quantified for each experimental condition by MTT assay. Mean ± SD, n = 3. * indicates a significant difference from vector control cells, P < 0.05.
Authors: Steffan T. Nawrocki, Ning Wang, Claudia M. Espitia, Harley Wu, Claudia Villa Celi, Julian Olea, Paniz Zarand, Homa Dadrastoussi, Hittu Matta, Sruthi Sureshkumar, Madison E. Gamble, Natalie L. Hakim, David Drum, Jack Angeles, Kaijin Wu, Jiang F. Zhong, Xuelian Chen, Alex Duong, Jennifer S. Carew, Kevin R. Kelly
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
OpenAlex ID: W7166065555
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