Figure 4 from PLK1 Inhibition Induces Synthetic Lethality in Fanconi Anemia Pathway–Deficient Acute Myeloid Leukemia

• DOI: 10.1158/2767-9764.29051621
• Publication Date: 2025-05-13T16:35:34Z
• Authors: Aditya S. Sheth; Ka-Kui Chan; Sheng Liu; Jun Wan; Steve P. Angus; Steven D. Rhodes; Dana K. Mitchell; Christopher Davis; Maya Ridinger; Peter J. Croucher; Amer M. Zeidan; Aruna Wijeratne; Shaomin Qian; Ngoc Tung Tran; Elizabeth A. Sier...

<p>Low-dose volasertib causes selective toxicity in primary AMLs with predicted pathogenic FA pathway mutations. <b>A,</b> Graph represents viability of primary patient CD34⁺ AML cells treated with 10 nmol/L volasertib for 5 days. <i>P</i> values were calculated by two‐way ANOVA. <b>B,</b> Panel below bar graph indicates predicted pathogenic FA pathway mutations in patient AML samples identified through WES. <b>C,</b> Graph represents Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway functional pathways that were significantly enriched among identified gene mutations (<i>P</i> value < 0.05). <b>D,</b> Top depicts the position of FANCA residue L1260 within the predicted H12A helix of the C-terminal domain. Protein structure was predicted using AlphaFold Protein Structure Database (version 2022-11-01, RRID: SCR_023662). Bottom shows conservation of L1260 residue (highlighted in yellow) across multiple species. <b>E,</b> Representative Western blot showing FANCA expression in HeLa <i>FANCA-</i>KO cell line transfected with empty vector, <i>FANCA</i>-WT, or <i>FANCA</i>-Mut(L1260P). Representative graph shows the mean ± SEM cell viability (%) of empty (<i>FANCA-</i>KO), <i>FANCA</i>-WT, and <i>FANCA</i>-Mut(L1260P) HeLa cells treated with MMC for 4 days. <i>P</i> values were calculated by two‐way ANOVA. <b>F,</b> Representative graph shows the mean ± SEM cell viability (%) of empty (<i>FANCA-</i>KO) and <i>FANCA</i>-WT vs. <i>FANCA</i>-Mut(L1260P) HeLa cells treated with volasertib for 3 days. <i>P</i> values were calculated by two‐way ANOVA. <b>G,</b> Representative Western blot of FAN1 expression in control cells (Scr.Ctrl) vs. FAN1-KD (shFAN1) HeLa cells. Representative graph shows the mean ± SEM cell viability (%) of shFAN1 cells vs. Scr.Ctrl. HeLa cells treated with volasertib for 3 days. For all cell lines, viability was measured by CellTiter-Glo assay. <i>P</i> values were calculated by two‐way ANOVA. All experiments were repeated at least 3 times. ns, not significant.</p>