Department of Human and Animal Cell Lines, Leibniz-Institute DSMZ, German Collection of Microorganisms and Cell Cultures, 38124 Braunschweig, Germany.
Int J Mol Sci. 2022 Oct 6;23(19):11874. doi: 10.3390/ijms231911874.
Homeobox genes encode transcription factors regulating basic developmental processes. They are arranged according to sequence similarities of their conserved homeobox in 11 classes, including TALE. Recently, we have reported the so-called TALE-code. This gene signature describes physiological expression patterns of all active TALE-class homeobox genes in the course of hematopoiesis. The TALE-code allows the evaluation of deregulated TALE homeobox genes in leukemia/lymphoma. Here, we extended the TALE-code to include the stages of pro-B-cells and pre-B-cells in early B-cell development. Detailed analysis of the complete lineage of B-cell differentiation revealed expression of TALE homeobox genes IRX1 and MEIS1 exclusively in pro-B-cells. Furthermore, we identified aberrant expression of IRX2, IRX3 and MEIS1 in patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) which originates from early B-cell progenitors. The data showed correlated activities of deregulated TALE-class members with particular BCP-ALL subtype markers, namely IRX2 with TCF3/E2A-fusions, IRX3 with ETV6/TEL-fusions, and MEIS1 with KMT2A/MLL-fusions. These correlations were also detected in BCP-ALL cell lines which served as experimental models. We performed siRNA-mediated knockdown experiments and reporter gene assays to analyze regulatory connections. The results showed mutual activation of IRX1 and TCF3. In contrast, IRX2 directly repressed wild-type TCF3 while the fusion gene TCF3::PBX1 lost the binding site for IRX2 and remained unaltered. IRX3 mutually activated fusion gene ETV6::RUNX1 while activating itself by aberrantly expressed transcription factor KLF15. Finally, KMT2A activated MEIS1 which in turn supported the expression of IRX3. In summary, we revealed normal TALE homeobox gene expression in early B-cell development and identified aberrant activities of IRX2, IRX3 and MEIS1 in particular subtypes of BCP-ALL. Thus, these TALE homeobox genes may serve as novel diagnostic markers and therapeutic targets.
同源盒基因编码转录因子，调节基本的发育过程。它们根据保守同源盒的序列相似性排列成 11 个类别，包括 TALE。最近，我们报道了所谓的 TALE 编码。这个基因特征描述了所有活跃的 TALE 类同源盒基因在造血过程中的生理表达模式。TALE 编码允许评估白血病/淋巴瘤中失调的 TALE 同源盒基因。在这里，我们将 TALE 编码扩展到包括早期 B 细胞发育中前 B 细胞和前 B 细胞的阶段。对 B 细胞分化完整谱系的详细分析显示，IRX1 和 MEIS1 这两个 TALE 同源盒基因仅在前 B 细胞中表达。此外，我们发现 B 细胞前体急性淋巴细胞白血病 (BCP-ALL) 患者中 IRX2、IRX3 和 MEIS1 的异常表达，BCP-ALL 起源于早期 B 细胞祖细胞。数据显示，失调的 TALE 类成员与特定的 BCP-ALL 亚型标志物之间存在关联的活性，即 IRX2 与 TCF3/E2A 融合，IRX3 与 ETV6/TEL 融合，MEIS1 与 KMT2A/MLL 融合。这些相关性也在 BCP-ALL 细胞系中检测到，这些细胞系作为实验模型。我们进行了 siRNA 介导的敲低实验和报告基因分析，以分析调节关系。结果表明，IRX1 和 TCF3 之间存在相互激活。相反，IRX2 直接抑制野生型 TCF3，而融合基因 TCF3::PBX1 失去了与 IRX2 的结合位点，没有改变。IRX3 相互激活融合基因 ETV6::RUNX1，同时通过异常表达的转录因子 KLF15 激活自身。最后，KMT2A 激活 MEIS1，MEIS1 反过来又支持 IRX3 的表达。总之，我们揭示了早期 B 细胞发育中正常的 TALE 同源盒基因表达，并确定了 IRX2、IRX3 和 MEIS1 在特定 BCP-ALL 亚型中的异常活性。因此，这些 TALE 同源盒基因可能成为新的诊断标志物和治疗靶点。
