Abstract 7111: Homoharringtonine is effective in treating acute lymphoblastic leukaemia via WEE1 downregulation and inducing DNA damage

Abstract

<p>Acute lymphoblastic leukaemia (ALL) is an aggressive haematolymphoid malignancy that originated from clonal mutations in lymphoid precursors. The prognosis is poor in adult patients and relapse/refractory disease is not uncommon which carries dismal prognosis. There is an urgent need to develop novel therapeutics. Homoharringtonine (HHT) is a plant alkaloid which can bind to ribosomal A-site and thus inhibit protein synthesis. It was used to treat acute myeloid leukaemia in China during 1980s. Herein, we conducted a study to explore the therapeutic efficacy and mechanism of action in ALL. T-ALL (DND-41, PEER) and B-ALL (PALL-2, SUP-B15) cell lines were treated with HHT for 24 and 72 hours. Cell viability was reduced at a time and dose-dependent manner in all cell lines we tested, with increased in percentage of apoptosis. Western blot showed upregulation of p53, with PARP and caspase 3 cleavages upon treating with HHT for 24 hours. Moreover, we observed WEE1 downregulation which allowed cell cycle progression through G2/M with damaged DNA. Comet assay showed evidence of DNA damage. Proteomics study by label-free protein quantitation showed downregulation of proteins involving in homologous recombination-mediated DNA repairing machinery, including BRCA1 and RAD51. The findings not only showed therapeutic efficacy of HHT in ALL, but also demonstrated the first evidence of DNA damage induced by HHT which might account for its therapeutic effects. Further studies will be conducted for delineating the mechanisms of DNA damage and its relationship with therapeutic efficacy.<br></p>