Acute myeloid leukemia (AML) remains a challenging hematological malignancy with poor prognosis and limited treatment options. Leukemic stem cells (LSCs) contribute to therapeutic failure, relapse, and adverse outcome. This study investigates the role of quiescence and related molecular mechanisms in AML pathogenesis and LSC functions to identify potential therapeutic targets. Transcriptomic analysis revealed that the LSC-enriched quiescent cell population has a distinct gene signature with prognostic relevance in patients with AML. Mechanistically, quiescent blasts exhibit increased autophagic activity, which contributes to their sustained viability. Proteomic profiling uncovered differential requirements for iron metabolism between quiescent and cycling cells, revealing a unique dependence of quiescent cells on ferritinophagy, a selective form of autophagy mediated by nuclear receptor coactivator 4 (NCOA4), which regulates iron bioavailability. We evaluated the therapeutic potential of inhibiting NCOA4-mediated ferritinophagy using genetic knockdown and chemical inhibition approaches. In vitro assays showed that suppression of NCOA4 was toxic to leukemic blasts, particularly the CD34 + CD38 − LSC-enriched population, without affecting normal CD34 + hematopoietic progenitors. In vivo studies using murine patient-derived xenograft (PDX) models of AML confirmed that NCOA4 inhibition reduced tumor burden and impaired LSC viability and self-renewal, indicating a specific vulnerability of these cells to ferritinophagy disruption. Our findings underscore the role of NCOA4-mediated ferritinophagy in maintaining LSC quiescence and function and suggest that targeting this pathway may be an effective therapeutic strategy for AML. This study highlights the potential of NCOA4 inhibition to improve AML outcomes and paves the way for future research and clinical development.

中文翻译：

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靶向铁蛋白吞噬会损害急性髓系白血病体外和体内模型中的静止癌症干细胞


急性髓系白血病（AML）仍然是一种具有挑战性的血液恶性肿瘤，预后不良，治疗选择有限。白血病干细胞 (LSC) 会导致治疗失败、复发和不良后果。本研究探讨了静止和相关分子机制在 AML 发病机制和 LSC 功能中的作用，以确定潜在的治疗靶点。转录组分析显示，富含 LSC 的静止细胞群具有独特的基因特征，与 AML 患者的预后相关。从机制上讲，静止的原始细胞表现出增强的自噬活性，这有助于它们的持续生存能力。蛋白质组分析揭示了静止细胞和循环细胞之间铁代谢的差异需求，揭示了静止细胞对铁蛋白自噬的独特依赖性，铁蛋白自噬是一种由核受体辅激活剂 4 (NCOA4) 介导的选择性形式的自噬，可调节铁的生物利用度。我们评估了使用基因敲低和化学抑制方法抑制 NCOA4 介导的铁蛋白自噬的治疗潜力。体外试验表明，抑制 NCOA4 对白血病母细胞具有毒性，尤其是 CD34 + CD38 -富含 LSC 的群体，不影响正常 CD34 +造血祖细胞。使用小鼠患者来源的 AML 异种移植 (PDX) 模型进行的体内研究证实，NCOA4 抑制可减轻肿瘤负荷并损害 LSC 活力和自我更新，表明这些细胞对铁蛋白吞噬破坏具有特定的脆弱性。 我们的研究结果强调了 NCOA4 介导的铁蛋白自噬在维持 LSC 静止和功能中的作用，并表明针对该途径可能是 AML 的有效治疗策略。这项研究强调了 NCOA4 抑制改善 AML 结局的潜力，并为未来的研究和临床开发铺平了道路。