Acute myeloid leukemia (AML) therapy is undergoing rapid development, but primary and acquired resistance to therapy complicates the prospect of a durable cure. Recent functional and single-cell multi-omics approaches have greatly expanded our knowledge of the diversity of lineage trajectories in AML settings. AML cells range from undifferentiated stem-like cells to more differentiated myeloid or megakaryocyte/erythroid cells. Current clinically relevant drugs predominantly target the myeloid progenitor lineage, while monocyte- or stem cell-like states can evade current AML treatment and may be targeted in the future with lineage-specific inhibitors. The extent of aberrant lineage plasticity upon therapeutic pressure in AML cells in conjunction with hijacking of normal differentiation pathways is still a poorly understood topic. Insights into the mechanisms of lineage plasticity of AML stem cells could identify both therapy-specific and cross-drug resistance pathways and reveal novel strategies to overcome them.

中文翻译：

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对抗耐药性的军备竞赛：白血病干细胞和谱系可塑性

急性髓系白血病（AML）治疗正在快速发展，但原发性和获得性耐药性使持久治愈的前景变得复杂。最近的功能和单细胞多组学方法极大地扩展了我们对 AML 谱系轨迹多样性的了解。AML 细胞范围从未分化的干细胞样细胞到分化程度更高的骨髓细胞或巨核细胞/红细胞。目前的临床相关药物主要针对骨髓祖细胞谱系，而单核细胞或干细胞样状态可以逃避当前的 AML 治疗，并可能在未来以谱系特异性抑制剂为目标。AML细胞治疗压力下异常谱系可塑性的程度以及正常分化途径的劫持仍然是一个知之甚少的话题。对 AML 干细胞谱系可塑性机制的深入了解可以识别治疗特异性和交叉耐药途径，并揭示克服这些途径的新策略。