Faculty of Medicine and Health Technology, Tampere Center for Child Health Research, Tampere University, Tampere, Finland.
The Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
Leuk Lymphoma. 2020 Dec;61(13):3089-3100. doi: 10.1080/10428194.2020.1804560. Epub 2020 Aug 24.
T-cell acute lymphoblastic leukemia (T-ALL) is a hematological malignancy driven by abnormal activity of transcription factors. Here we report an aberrant expression of the developmental transcription factor in the TAL1-subtype of T-ALL. Our results demonstrate that the binding of TAL1 and GATA3 transcription factors into an upstream enhancer element directly regulates SIX6 expression. High expression of SIX6 was associated with inferior event-free survival within three independent patient cohorts. At a functional level, CRISPR-Cas9-mediated knockout of the gene in TAL1 positive Jurkat cells induced changes in genes associated with the mTOR-, K-RAS-, and TNFα-related molecular signatures but did not impair cell proliferation or viability. There was also no acceleration of T-ALL development within a Myc driven zebrafish tumor model . Taken together, our results show that SIX6 belongs to the TAL1 regulatory gene network in T-ALL but is alone insufficient to influence the development or maintenance of T-ALL.
T 细胞急性淋巴细胞白血病（T-ALL）是一种由转录因子异常激活驱动的血液系统恶性肿瘤。在这里，我们报告了发育转录因子 SIX6 在 TAL1 亚型 T-ALL 中的异常表达。我们的研究结果表明，TAL1 和 GATA3 转录因子的结合直接调控 SIX6 的表达。在三个独立的患者队列中，SIX6 的高表达与无事件生存不良相关。在功能水平上，CRISPR-Cas9 介导的 TAL1 阳性 Jurkat 细胞中 SIX6 基因的敲除诱导了与 mTOR、K-RAS 和 TNFα 相关分子特征相关的基因发生变化，但不损害细胞增殖或活力。在 Myc 驱动的斑马鱼肿瘤模型中，也没有加速 T-ALL 的发展。综上所述，我们的研究结果表明，SIX6 属于 T-ALL 中的 TAL1 调节基因网络，但单独不足以影响 T-ALL 的发生或维持。
