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 Mar 16;23(6):3192. doi: 10.3390/ijms23063192.
Homeobox genes encode transcription factors that control basic developmental decisions. Knowledge of their hematopoietic activities casts light on normal and malignant immune cell development. Recently, we constructed the so-called lymphoid TALE-code that codifies expression patterns of all active TALE class homeobox genes in early hematopoiesis and lymphopoiesis. Here, we present the corresponding myeloid TALE-code to extend this gene signature, covering the entire hematopoietic system. The collective data showed expression patterns for eleven TALE homeobox genes and highlighted the exclusive expression of IRX1 in megakaryocyte-erythroid progenitors (MEPs), implicating this TALE class member in a specific myeloid differentiation process. Analysis of public profiling data from acute myeloid leukemia (AML) patients revealed aberrant activity of IRX1 in addition to IRX3 and IRX5, indicating an oncogenic role for these TALE homeobox genes when deregulated. Screening of RNA-seq data from 100 leukemia/lymphoma cell lines showed overexpression of IRX1, IRX3, and IRX5 in megakaryoblastic and myelomonocytic AML cell lines, chosen as suitable models for studying the regulation and function of these homeo-oncogenes. Genomic copy number analysis of IRX-positive cell lines demonstrated chromosomal amplification of the neighboring IRX3 and IRX5 genes at position 16q12 in MEGAL, underlying their overexpression in this cell line model. Comparative gene expression analysis of these cell lines revealed candidate upstream factors and target genes, namely the co-expression of GATA1 and GATA2 together with IRX1, and of BMP2 and HOXA10 with IRX3/IRX5. Subsequent knockdown and stimulation experiments in AML cell lines confirmed their activating impact in the corresponding IRX gene expression. Furthermore, we demonstrated that IRX1 activated KLF1 and TAL1, while IRX3 inhibited GATA1, GATA2, and FST. Accordingly, we propose that these regulatory relationships may represent major physiological and oncogenic activities of IRX factors in normal and malignant myeloid differentiation, respectively. Finally, the established myeloid TALE-code is a useful tool for evaluating TALE homeobox gene activities in AML.
同源盒基因编码转录因子，可控制基本的发育决策。了解其造血活性可以阐明正常和恶性免疫细胞的发育。最近，我们构建了所谓的淋巴 TALE 编码，该编码编码了早期造血和淋巴发生中所有活性 TALE 类同源盒基因的表达模式。在这里，我们提出了相应的骨髓 TALE 编码以扩展该基因特征，涵盖整个造血系统。汇总数据显示了十一个 TALE 同源盒基因的表达模式，并突出了 IRX1 在巨核细胞-红细胞祖细胞（MEP）中的特异性表达，暗示该 TALE 类成员参与了特定的骨髓分化过程。对急性髓细胞性白血病（AML）患者的公共分析数据的分析揭示了 IRX1 的异常活性，除了 IRX3 和 IRX5 之外，表明这些 TALE 同源盒基因在失调时具有致癌作用。对 100 个白血病/淋巴瘤细胞系的 RNA-seq 数据进行筛选显示，IRX1、IRX3 和 IRX5 在巨核细胞和成髓细胞性 AML 细胞系中过表达，这些细胞系被选为研究这些同源癌基因的调控和功能的合适模型。IRX 阳性细胞系的基因组拷贝数分析表明，IRX3 和 IRX5 基因在 16q12 位置的染色体扩增，这是该细胞系模型中它们过表达的基础。对这些细胞系的比较基因表达分析揭示了候选上游因子和靶基因，即 IRX1 与 GATA1 和 GATA2 的共表达，以及 IRX3/IRX5 与 BMP2 和 HOXA10 的共表达。随后在 AML 细胞系中的敲低和刺激实验证实了它们对相应 IRX 基因表达的激活作用。此外，我们证明了 IRX1 激活了 KLF1 和 TAL1，而 IRX3 抑制了 GATA1、GATA2 和 FST。因此，我们提出这些调节关系可能分别代表 IRX 因子在正常和恶性骨髓分化中的主要生理和致癌活性。最后，建立的骨髓 TALE 编码是评估 AML 中 TALE 同源盒基因活性的有用工具。
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