Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Department of Pathophysiology and Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai, 200025, China.
Biodynamic Optical Imaging Center (BIOPIC), School of Life Sciences, Peking University, Beijing, China.
Cell Death Dis. 2018 May 1;9(5):526. doi: 10.1038/s41419-018-0600-3.
Somatic cells acquire stem cell-like properties during cancerous transformation; however, mechanisms through which committed cells develop stemness and malignancy remain largely unknown. Here we uncovered upregulated stem cell program in leukaemic lymphoblasts of patients with IKZF1 alterations by analysing the archived gene-expression profiling datasets. We then used a frequent IKZF1 deletion, IK6, as a model via transduction into human primitive haematopoietic cells, followed by xenotransplantation in mice. Immunophenotypically defined stem, pro-B, and immature/mature (IM/M)-B cells were collected from primary recipients for functional assay and transcriptome profiling. Successful reconstitution in secondary recipient mice revealed the stemness of IK6 pro-B and IM/M-B cells. Upregulated stemness and malignancy programs in IK6 cells confirmed IK6 effects. Interestingly, these programs corresponded to distinct canonical pathways. Remarkably, the pathway profile mapped in the modelled cells well mirrored that in patients' leukaemic cells; therefore, our study provides a seminal insight into the cancerous reprogramming of somatic cells.
体细胞在癌变过程中获得类似干细胞的特性；然而， committed cells 发展为干细胞和恶性肿瘤的机制在很大程度上仍然未知。在这里，我们通过分析存档的基因表达谱数据集，发现 IKZF1 改变的白血病淋巴母细胞中上调的干细胞程序。然后，我们使用频繁的 IKZF1 缺失 IK6 通过转导到人类原始造血细胞，然后进行异种移植到小鼠中作为模型。从原发性受者中收集免疫表型定义的干细胞、前 B 细胞和未成熟/成熟 (IM/M)-B 细胞进行功能测定和转录组谱分析。在二级受者小鼠中成功重建揭示了 IK6 前 B 和 IM/M-B 细胞的干细胞特性。IK6 细胞中上调的干细胞和恶性肿瘤程序证实了 IK6 的作用。有趣的是，这些程序对应于不同的经典途径。值得注意的是，模型细胞中的途径图谱很好地反映了患者白血病细胞中的图谱；因此，我们的研究为体细胞的癌变重编程提供了重要的见解。
