Department of Medical Biochemistry, Faculty of Medicine, Al-Azhar University, Cairo, Egypt.
Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
Int J Hematol. 2023 Jun;117(6):830-838. doi: 10.1007/s12185-023-03605-y. Epub 2023 May 2.
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.
癌症在细胞层面非常罕见，但在身体层面却是一种常见疾病，因为有三分之一的人死于癌症。体内一小部分细胞具有构成允许特定基因突变引发癌症的宽容窗口的细胞特征。宽容窗口的意义讽刺地最好体现在生成 t(8;21) 急性髓系白血病 (AML) 动物模型的大量失败上。几十年来，t(8;21) 产生的 RUNX1-ETO 融合基因已被引入各种类型的造血细胞中，主要是在成年期，在小鼠中；然而，之前所有的尝试都未能成功生成可追踪的 AML 模型。相比之下，我们最近通过在儿童造血干细胞 (HSCs) 中特异性引入 RUNX1-ETO 成功地诱导出具有人类患者所见临床特征的 AML。在小鼠中的这一结果与人类 t(8;21) 患者的青少年和年轻成人 (AYA) 发病一致，并表明儿童 HSCs 构成了 RUNX1-ETO 白血病发生的宽容窗口。如果通过药理学诱导宽容窗口的丧失，癌细胞可能会被选择性靶向。这种宽容窗口调节剂可能成为一种新型治疗药物。
