ABSTRACT

Minimal residual disease (MRD) refers to a low number of cells that persist anti-cancer treatment and is the major cause of relapse in solid cancers and leukemias. In chronic myeloid leukemia (CML), a paradigm for stem cell-driven cancer, MRD is maintained by tyrosine kinase inhibitor (TKI)-insensitive leukemic stem cells (LSCs), which may rely on fundamental metabolic processes to resist drug treatment. Macroautophagy/autophagy is a cytoprotective process that has been highlighted as critical for sustaining LSC survival during TKI treatment in robust experimental models of CML. Our recent study shows that the autophagy-initiating kinase ULK1 is required for maintaining energy and redox balance in CML LSCs. Pharmacological inhibition of ULK1 results in stress-induced differentiation of LSCs, rendering them sensitive to TKI treatment, uncovering a promising strategy for selective eradication of LSCs in CML patients.

Abbreviations CML: chronic myeloid leukemia; LSC: leukemic stem cell; MAPK: mitogen-activated protein kinase; MRD: minimal residual disease; TKI: tyrosine kinase inhibitor

 抽象的

微小残留病（MRD）是指持续抗癌治疗的细胞数量较少，是实体癌和白血病复发的主要原因。在慢性粒细胞白血病 (CML)（干细胞驱动癌症的一种范例）中，MRD 由酪氨酸激酶抑制剂 (TKI) 不敏感的白血病干细胞 (LSC) 维持，这些细胞可能依赖基本代谢过程来抵抗药物治疗。巨自噬/自噬是一种细胞保护过程，在稳健的 CML 实验模型中，TKI 治疗期间，它对于维持 LSC 存活至关重要。我们最近的研究表明，自噬启动激酶 ULK1 是维持 CML LSC 能量和氧化还原平衡所必需的。 ULK1 的药理抑制会导致应激诱导的 LSC 分化，使它们对 TKI 治疗敏感，从而揭示了选择性根除 CML 患者 LSC 的有前途的策略。

缩写CML：慢性粒细胞白血病； LSC：白血病干细胞； MAPK：丝裂原激活蛋白激酶； MRD：微小残留病； TKI：酪氨酸激酶抑制剂