Mets Evelien, Van Peer Gert, Van der Meulen Joni, Boice Michael, Taghon Tom, Goossens Steven, Mestdagh Pieter, Benoit Yves, De Moerloose Barbara, Van Roy Nadine, Poppe Bruce, Vandesompele Jo, Wendel Hans-Guido, Van Vlierberghe Pieter, Speleman Frank, Rondou Pieter
Center for Medical Genetics, Ghent University, Belgium.
Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Haematologica. 2014 Aug;99(8):1326-33. doi: 10.3324/haematol.2013.099515. Epub 2014 Jun 3.
T-cell acute lymphoblastic leukemia arises from the leukemic transformation of developing thymocytes and results from cooperative genetic lesions. Inactivation of the PHF6 gene is frequently observed in T-cell acute lymphoblastic leukemia, suggesting an important tumor suppressive role for PHF6 in the pathobiology of this leukemia. Although the precise function of PHF6 is still unknown, this gene is most likely involved in chromatin regulation, a strongly emerging theme in T-cell acute lymphoblastic leukemia. In this context, our previous description of a cooperative microRNA regulatory network controlling several well-known T-cell acute lymphoblastic leukemia tumor suppressor genes, including PHF6, is of great importance. Given the high frequency of PHF6 lesions in T-cell acute lymphoblastic leukemia and the integration of PHF6 in this microRNA regulatory network, we aimed to identify novel oncogenic microRNAs in T-cell acute lymphoblastic leukemia which suppress PHF6. To this end, we performed an unbiased PHF6 3'UTR-microRNA library screen and combined the results with microRNA profiling data of samples from patients with T-cell acute lymphoblastic leukemia and normal thymocyte subsets. We selected miR-128-3p as a candidate PHF6-targeting, oncogenic microRNA and demonstrated regulation of PHF6 expression upon modulation of this microRNA in T-cell acute lymphoblastic leukemia cell lines. In vivo evidence of an oncogenic role of this microRNA in T-cell acute lymphoblastic leukemia was obtained through accelerated leukemia onset in a NOTCH1-induced T-cell acute lymphoblastic leukemia mouse model upon miR-128-3p over-expression. We conclude that miR-128-3p is a strong novel candidate oncogenic microRNA in T-cell acute lymphoblastic leukemia which targets the PHF6 tumor suppressor gene.
T细胞急性淋巴细胞白血病源于发育中的胸腺细胞的白血病转化，是由协同的基因损伤导致的。PHF6基因的失活在T细胞急性淋巴细胞白血病中经常被观察到，这表明PHF6在这种白血病的病理生物学中具有重要的肿瘤抑制作用。尽管PHF6的确切功能仍然未知，但该基因很可能参与染色质调控，这是T细胞急性淋巴细胞白血病中一个新兴的重要主题。在这种背景下，我们之前对一个控制包括PHF6在内的几个著名的T细胞急性淋巴细胞白血病肿瘤抑制基因的协同微小RNA调控网络的描述非常重要。鉴于PHF6损伤在T细胞急性淋巴细胞白血病中的高频率以及PHF6在这个微小RNA调控网络中的整合，我们旨在鉴定T细胞急性淋巴细胞白血病中抑制PHF6的新型致癌微小RNA。为此，我们进行了无偏向性的PHF6 3'UTR-微小RNA文库筛选，并将结果与T细胞急性淋巴细胞白血病患者和正常胸腺细胞亚群样本的微小RNA谱数据相结合。我们选择miR-128-3p作为靶向PHF6的致癌微小RNA候选物，并证明在T细胞急性淋巴细胞白血病细胞系中调节这种微小RNA时，PHF6表达受到调控。通过在NOTCH1诱导的T细胞急性淋巴细胞白血病小鼠模型中过表达miR-128-3p后加速白血病发病，获得了这种微小RNA在T细胞急性淋巴细胞白血病中致癌作用的体内证据。我们得出结论，miR-128-3p是T细胞急性淋巴细胞白血病中一个强有力的新型致癌微小RNA候选物，它靶向PHF6肿瘤抑制基因。
