Nagel Stefan, Ehrentraut Stefan, Meyer Corinna, Kaufmann Maren, Drexler Hans G, MacLeod Roderick A F
Department of Human and Animal Cell Lines, Leibniz-Institute DSMZ - German Collection of Microorganisms and Cell Cultures , Braunschweig , Germany.
Leuk Lymphoma. 2015 Feb;56(2):480-91. doi: 10.3109/10428194.2014.924119. Epub 2014 Jun 12.
In T-cell acute lymphoblastic leukemia (T-ALL), several members of the NK-like (NKL) homeobox genes are aberrantly expressed. Here, we have analyzed the activity of NKL homeobox gene MSX1 using pediatric T-ALL in silico data, detecting overexpression in 11% of patients. Quantification of MSX1 transcripts in a panel of 24 T-ALL cell lines demonstrated overexpression in two examples. Comparative expression profiling indicated inhibition of the bone morphogenetic protein (BMP) signaling pathway, which was shown to inhibit MSX1 transcription. In the LOUCY cell line we identified conspicuous expression of CHRDL1 encoding a BMP inhibitor which mediated activation of MSX1. Promoter analyses demonstrated activation of CHRDL1 by oncogenic PITX1. Furthermore, knockdown and overexpression studies of hematopoietic transcription factors demonstrated that GATA2 and FOXC1 mediate activation and GATA3, LEF1, TAL1 and TOX repression of MSX1 transcription. Collectively, our findings suggest that MSX1 is physiologically restricted to lymphoid progenitors. The identification of deregulated BMP signaling may provide novel therapeutic options for the treatment of T-ALL.
在T细胞急性淋巴细胞白血病（T-ALL）中，NK样（NKL）同源框基因的几个成员表达异常。在此，我们利用儿科T-ALL的电子数据对NKL同源框基因MSX1的活性进行了分析，发现11%的患者存在过表达。对一组24种T-ALL细胞系中MSX1转录本的定量分析表明，有两个样本存在过表达。比较表达谱分析表明骨形态发生蛋白（BMP）信号通路受到抑制，该通路被证明可抑制MSX1转录。在LOUCY细胞系中，我们发现编码BMP抑制剂的CHRDL1有明显表达，它介导了MSX1的激活。启动子分析表明致癌性PITX1可激活CHRDL1。此外，造血转录因子的敲低和过表达研究表明，GATA2和FOXC1介导MSX1转录的激活，而GATA3、LEF1、TAL1和TOX介导其抑制。总的来说，我们的研究结果表明MSX1在生理上局限于淋巴祖细胞。BMP信号通路失调的鉴定可能为T-ALL的治疗提供新的治疗选择。
