Leukaemic alterations of IKZF1 prime stemness and malignancy programs in human lymphocytes
Leukaemic alterations of IKZF1 prime stemness and malignancy programs in human lymphocytes
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人类淋巴细胞中 IKZF1 主要干细胞的白血病改变和恶性肿瘤程序
DOI：
10.1038/s41419-018-0600-3
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发表时间：
2018-05-09
影响因子：
9
通讯作者：
Hong, Deng-Li
中科院分区：
文献类型：
--
作者：
Li, Zhen;Li, Shui-Ping;Hong, Deng-Li
体细胞在癌变过程中获得干细胞样特性;然而，定向细胞发展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，发现了IKZF 1改变患者白血病淋巴母细胞中干细胞程序上调。然后，我们使用了一个频繁IKZF 1缺失，IK 6，作为一个模型，通过转导到人类原始造血细胞，然后在小鼠异种移植。从原代受体收集免疫表型确定的干细胞、前B细胞和未成熟/成熟（IM/M）-B细胞，用于功能测定和转录组分析。在第二受体小鼠中的成功重建揭示了IK 6 +pro-B和IM/M-B细胞的干性。在IK 6+细胞中上调的干性和恶性程序证实了IK 6的作用。有趣的是，这些程序对应于不同的典型途径。值得注意的是，在模型细胞中映射的通路谱很好地反映了患者白血病细胞中的通路谱;因此，我们的研究为体细胞的癌性重编程提供了开创性的见解。
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 withIKZF1alterations by analysing the archived gene-expression profiling datasets. We then used a frequentIKZF1deletion, 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.