Department of Human and Animal Cell Lines, Leibniz-Institute DSMZ, 38124 Braunschweig, Germany.
Genes (Basel). 2024 Jul 24;15(8):978. doi: 10.3390/genes15080978.
Pro-B- and pre-B-cells are consecutive entities in early B-cell development, representing cells of origin for B-cell precursor acute lymphoid leukemia (BCP-ALL). Normal B-cell differentiation is critically regulated by specific transcription factors (TFs). Accordingly, TF-encoding genes are frequently deregulated or mutated in BCP-ALL. Recently, we described TF-codes which delineate physiological activities of selected groups of TF-encoding genes in hematopoiesis including B-cell development. Here, we exploited these codes to uncover regulatory connections between particular TFs in pro-B- and pre-B-cells via an analysis of developmental TFs encoded by NKL and TALE homeobox genes and by ETS and T-box genes. Comprehensive expression analyses in BCP-ALL cell lines helped identify validated models to study their mutual regulation in vitro. Knockdown and overexpression experiments and subsequent RNA quantification of TF-encoding genes in selected model cell lines revealed activating, inhibitory or absent connections between nine TFs operating in early B-cell development, including HLX, MSX1, IRX1, MEIS1, ETS2, ERG, SPIB, EOMES, and TBX21. In addition, genomic profiling revealed BCP-ALL subtype-specific copy number alterations of at 21q22, while a deletion of the TGFbeta-receptor gene at 3p24 resulted in an upregulation of . Finally, we combined the data to uncover gene regulatory networks which control normal differentiation of early B-cells, collectively endorsing more detailed evaluation of BCP-ALL subtypes.
前 B 细胞和前体 B 细胞是早期 B 细胞发育中的连续实体，代表 B 细胞前体急性淋巴细胞白血病（BCP-ALL）的起源细胞。正常 B 细胞分化受到特定转录因子（TF）的严格调控。因此，BCP-ALL 中经常出现 TF 编码基因的失调或突变。最近，我们描述了 TF 编码基因的 TF 代码，这些代码描绘了包括 B 细胞发育在内的造血中选定 TF 编码基因群体的生理活性。在这里，我们通过分析 NKL 和 TALE 同源盒基因以及 ETS 和 T 盒基因编码的发育 TF，利用这些代码揭示了前 B 细胞和前体 B 细胞中特定 TF 之间的调节关系。在 BCP-ALL 细胞系中的全面表达分析有助于确定验证模型，以在体外研究它们的相互调节。在选定的模型细胞系中敲低和过表达实验以及随后的 TF 编码基因 RNA 定量显示，在早期 B 细胞发育中起作用的九个 TF 之间存在激活、抑制或不存在的连接，包括 HLX、MSX1、IRX1、MEIS1、ETS2、ERG、SPIB、EOMES 和 TBX21。此外，基因组分析显示 21q22 上存在 BCP-ALL 亚型特异性拷贝数改变，而 3p24 上 TGFbeta 受体基因 的缺失导致 的上调。最后，我们将数据结合起来，揭示了控制早期 B 细胞正常分化的基因调控网络，共同支持对 BCP-ALL 亚型进行更详细的评估。
