Leukemia is characterized by oncogenic lesions that result in a block of differentiation, whereas phenotypic plasticity is retained. A better understanding of how these two phenomena arise during leukemogenesis in humans could help inform diagnosis and treatment strategies. Here, we leveraged the well-defined differentiation states during T-cell development to pinpoint the initiation of T-cell acute lymphoblastic leukemia (T-ALL), an aggressive form of childhood leukemia, and study the emergence of phenotypic plasticity. Single-cell whole genome sequencing of leukemic blasts was combined with multiparameter flow cytometry to couple cell identity and clonal lineages. Irrespective of genetic events, leukemia-initiating cells altered their phenotypes by differentiation and dedifferentiation. The construction of the phylogenies of individual leukemias using somatic mutations revealed that phenotypic diversity is reflected by the clonal structure of cancer. The analysis also indicated that the acquired phenotypes are heritable and stable. Together, these results demonstrate a transient period of plasticity during leukemia initiation, where phenotypic switches seem unidirectional. Significance: A method merging multicolor flow cytometry with single-cell whole genome sequencing to couple cell identity with clonal lineages uncovers differentiation-state plasticity in leukemia, reconciling blocked differentiation with phenotypic plasticity in cancer.

中文翻译：

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短暂分化状态可塑性发生在急性淋巴细胞白血病起始过程中。


白血病的特征是致癌病变导致分化受阻，而表型可塑性得以保留。更好地了解这两种现象在人类白血病发生过程中是如何出现的，有助于为诊断和治疗策略提供信息。在这里，我们利用 T 细胞发育过程中明确的分化状态来查明 T 细胞急性淋巴细胞白血病 (T-ALL)（一种儿童白血病的侵袭性形式）的起始，并研究表型可塑性的出现。白血病母细胞的单细胞全基因组测序与多参数流式细胞术相结合，以耦合细胞身份和克隆谱系。无论遗传事件如何，白血病起始细胞都会通过分化和去分化改变其表型。使用体细胞突变构建个体白血病的系统发育表明，癌症的克隆结构反映了表型多样性。分析还表明获得的表型是可遗传的且稳定的。总之，这些结果证明了白血病发生过程中存在短暂的可塑性时期，其中表型转换似乎是单向的。意义：一种将多色流式细胞术与单细胞全基因组测序相结合，将细胞身份与克隆谱系结合起来的方法，揭示了白血病的分化状态可塑性，从而协调了癌症中的分化受阻与表型可塑性。