Statins Kill Acute Myeloid Leukemia Cells through Low-Density Lipoprotein Receptor-Mediated Unfolded Protein Response Activation

作者：Yohei Yasuda, Yuta Fukui, Ken Morita, Muzhapaer Mubalizi, Hiroki Hayashida, Toshiya Hino, Yosuke Masamoto, Mineo Kurokawa · 发表于：Blood · 年份：2024 · DOI：10.1182/blood-2024-198761 · 被引用次数：1 · 研究领域：Computational Drug Discovery Methods、Cancer, Lipids, and Metabolism、Lipoproteins and Cardiovascular Health

Statins, widely known for their cholesterol-lowering properties, have also shown anti-tumor effects, including against acute myeloid leukemia (AML) cells. Previously, most evidence for these effects came from in vitro studies. However, the SWOG S0919 trial, which evaluated a combination of idarubicin, cytarabine, and pravastatin in relapsed/refractory AML cases, reported a high complete response (CR/CRi) rate of 75%. Moreover, a recent retrospective analysis of a large national cohort revealed that statin use in patients with myelodysplastic syndromes was associated with a reduced risk of AML progression and prolonged overall survival. These studies have rekindled interest in the anti-leukemic effects of statins. Nevertheless, the precise mechanisms underlying these effects remain unclear. To elucidate these mechanisms, we conducted a genome-wide CRISPR-Cas9 knockout screening using THP-1 cells, a representative AML cell line, with or without statin treatment. The cells were cultured in the presence of either 2µM atorvastatin, 2µM fluvastatin, or dimethyl sulfoxide (DMSO) as a control for 20 days. The screening analysis identified several key genes that are associated with statin-induced proliferation suppression. Notably, LDLR (low-density lipoprotein receptor) and LDLRAP1 (LDLR adaptor protein 1) were among the top hits, with false discovery rate (FDR) < 0.01 and log2-fold change (LFC) > 4. Conversely, MYLIP (myosin regulatory light chain interacting protein),...