Childhood hematopoietic stem cells constitute the permissive window for RUNX1-ETO leukemogenesis
Childhood hematopoietic stem cells constitute the permissive window for RUNX1-ETO leukemogenesis
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DOI：
10.1007/s12185-023-03605-y
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发表时间：
2023-05-02
影响因子：
2.1
通讯作者：
Osato，Motomi
中科院分区：
文献类型：
--
作者：
Abdallah，Mohamed Gaber;Teoh，Vania Swee Imm;Osato，Motomi
癌症在细胞水平上是一种非常罕见的事件，尽管它在身体水平上是一种常见的疾病，因为三分之一的人死于癌症。体内的一小部分细胞具有细胞特征，这些特征构成了特定遗传变化诱发癌症的容许窗口。具有讽刺意味的是，在产生具有t（8;21）的急性髓性白血病（AML）动物模型中的大量失败最好地显示了容许窗口的重要性。几十年来，由t（8;21）产生的RUNX 1-ETO融合基因已被引入小鼠的各种类型的造血细胞中，主要是在成年阶段;然而，所有先前的尝试都未能产生易处理的AML模型。与此形成鲜明对比的是，我们最近通过在儿童造血干细胞（HSC）中特异性引入RUNX 1-ETO，成功诱导了具有人类患者临床特征的AML。小鼠中的这一结果与人类t（8;21）患者中的青少年和青年（AYA）发病一致，并表明儿童期HSC构成了RUNX 1-ETO白血病发生的容许窗口。如果一个允许窗口的损失被诱导，癌细胞可能会被选择性地靶向。这种允许的窗口修饰剂可以作为一种新型治疗药物。
Cancer is a very rare event at the cellular level, although it is a common disease at the body level as one third of humans die of cancer. A small subset of cells in the body harbor the cellular features that constitute a permissive window for a particular genetic change to induce cancer. The significance of a permissive window is ironically best shown by a large number of failures in generating the animal model for acute myeloid leukemia (AML) with t(8;21). Over the decades, the RUNX1-ETO fusion gene created by t(8;21) has been introduced into various types of hematopoietic cells, largely at adult stage, in mice; however, all the previous attempts failed to generate tractable AML models. In stark contrast, we recently succeeded in inducing AML with the clinical features seen in human patients by specifically introducing RUNX1-ETO in childhood hematopoietic stem cells (HSCs). This result in mice is consistent with adolescent and young adult (AYA) onset in human t(8;21) patients, and suggests that childhood HSCs constitute the permissive window for RUNX1-ETO leukemogenesis. If loss of a permissive window is induced pharmacologically, cancer cells might be selectively targeted. Such a permissive window modifier may serve as a novel therapeutic drug.