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A Double Negative Loop Comprising ETV6/RUNX1 and MIR181A1 Contributes to Differentiation Block in t(12;21)-Positive Acute Lymphoblastic Leukemia.
PLOS ONE ( IF 3.7 ) Pub Date : 2015-11-19 , DOI: 10.1371/journal.pone.0142863
Yung-Li Yang , Ching-Tzu Yen , Chen-Hsueh Pai , Hsuan-Yu Chen , Sung-Liang Yu , Chien-Yu Lin , Chung-Yi Hu , Shiann-Tarng Jou , Dong-Tsamn Lin , Shu-Rung Lin , Shu-Wha Lin

Childhood acute lymphoblastic leukemia (ALL) with t(12;21), which results in expression of the ETV6/RUNX1 fusion gene, is the most common chromosomal lesion in precursor-B (pre-B) ALL. We identified 17 microRNAs that were downregulated in ETV6/RUNX1+ compared with ETV6/RUNX1- clinical samples. Among these microRNAs, miR-181a-1 was the most significantly reduced (by ~75%; P < 0.001). Using chromatin immunoprecipitation, we demonstrated that ETV6/RUNX1 directly binds the regulatory region of MIR181A1, and knockdown of ETV6/RUNX1 increased miR-181a-1 level. We further showed that miR-181a (functional counterpart of miR-181a-1) could target ETV6/RUNX1 and cause a reduction in the level of the oncoprotein ETV6/RUNX1, cell growth arrest, an increase in apoptosis, and induction of cell differentiation in ETV6/RUNX1+ cell line. Moreover, ectopic expression of miR-181a also resulted in decreased CD10 hyperexpression in ETV6/RUNX1+ primary patient samples. Taken together, our results demonstrate that MIR181A1 and ETV6/RUNX1 regulate each other, and we propose that a double negative loop involving MIR181A1 and ETV6/RUNX1 may contribute to ETV6/RUNX1-driven arrest of differentiation in pre-B ALL.

中文翻译:

包含ETV6 / RUNX1和MIR181A1的双负循环有助于t(12; 21)-阳性急性淋巴细胞白血病中的分化阻滞。

儿童期t(12; 21)导致ETV6 / RUNX1融合基因表达的急性淋巴细胞白血病(ALL)是前体B(pre-B)ALL中最常见的染色体病变。与ETV6 / RUNX1临床样品相比,我们鉴定了ETV6 / RUNX1 +中下调的17个microRNA。在这些microRNA中,miR-181a-1的减少幅度最大(降低了〜75%; P <0.001)。使用染色质免疫沉淀,我们证明了ETV6 / RUNX1直接结合MIR181A1的调控区域,而敲低ETV6 / RUNX1则增加了miR-181a-1的水平。我们进一步表明,miR-181a(miR-181a-1的功能对应物)可以靶向ETV6 / RUNX1,并导致癌蛋白ETV6 / RUNX1的水平降低,细胞生长停滞,凋亡增加以及诱导细胞分化在ETV6 / RUNX1 +细胞系中。而且,miR-181a的异位表达还导致ETV6 / RUNX1 +主要患者样品中CD10过表达降低。两者合计,我们的结果表明MIR181A1和ETV6 / RUNX1相互调节,并且我们建议涉及MIR181A1和ETV6 / RUNX1的双负环可能有助于ETV6 / RUNX1驱动的前B ALL分化的停止。
更新日期:2019-11-01
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