Department of Genetics, Institute for Experimental Medicine, Istanbul University, Istanbul, Turkey.
Department of Pediatrics Hematology, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey.
Blood Cancer J. 2014 Mar 14;4(3):e192. doi: 10.1038/bcj.2014.12.
WNT signaling has been implicated in the regulation of hematopoietic stem cells and plays an important role during T-cell development in thymus. Here we investigated WNT pathway activation in childhood T-cell acute lymphoblastic leukemia (T-ALL) patients. To evaluate the potential role of WNT signaling in T-cell leukomogenesis, we performed expression analysis of key components of WNT pathway. More than 85% of the childhood T-ALL patients showed upregulated β-catenin expression at the protein level compared with normal human thymocytes. The impact of this upregulation was reflected in high expression of known target genes (AXIN2, c-MYC, TCF1 and LEF). Especially AXIN2, the universal target gene of WNT pathway, was upregulated at both mRNA and protein levels in ∼40% of the patients. When β-CATENIN gene was silenced by small interfering RNA, the cancer cells showed higher rates of apoptosis. These results demonstrate that abnormal WNT signaling activation occurs in a significant fraction of human T-ALL cases independent of known T-ALL risk factors. We conclude that deregulated WNT signaling is a novel oncogenic event in childhood T-ALL.
WNT 信号通路在造血干细胞的调控中起重要作用，并在胸腺 T 细胞发育过程中发挥重要作用。本研究旨在探讨 WNT 通路激活在儿童 T 细胞急性淋巴细胞白血病（T-ALL）中的作用。为评估 WNT 信号在 T 细胞白血病发生中的潜在作用，我们对 WNT 通路关键成分的表达进行了分析。与正常人类胸腺细胞相比，超过 85%的儿童 T-ALL 患者在蛋白水平上表现出β-catenin 的表达上调。这种上调的影响反映在已知靶基因（AXIN2、c-MYC、TCF1 和 LEF）的高表达上。特别是 AXIN2，WNT 通路的通用靶基因，在约 40%的患者中同时在 mRNA 和蛋白水平上均上调。当用小干扰 RNA 沉默β-CATENIN 基因时，癌细胞的凋亡率更高。这些结果表明，异常的 WNT 信号激活发生在相当一部分人类 T-ALL 病例中，与已知的 T-ALL 危险因素无关。我们得出结论，WNT 信号的失调是儿童 T-ALL 的一种新的致癌事件。
