Yang Yung-Li, Yen Ching-Tzu, Pai Chen-Hsueh, Chen Hsuan-Yu, Yu Sung-Liang, Lin Chien-Yu, Hu Chung-Yi, Jou Shiann-Tarng, Lin Dong-Tsamn, Lin Shu-Rung, Lin Shu-Wha
Departments of Laboratory Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.
Departments of Pediatrics, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.
PLoS One. 2015 Nov 18;10(11):e0142863. doi: 10.1371/journal.pone.0142863. eCollection 2015.
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.
伴有t(12;21)的儿童急性淋巴细胞白血病（ALL）会导致ETV6/RUNX1融合基因的表达，这是前体B（pre-B）ALL中最常见的染色体病变。我们鉴定出17种在ETV6/RUNX1阳性临床样本中相对于ETV6/RUNX1阴性临床样本下调的微小RNA。在这些微小RNA中，miR-181a-1的减少最为显著（约75%；P < 0.001）。通过染色质免疫沉淀，我们证明ETV6/RUNX1直接结合MIR181A1的调控区域，敲低ETV6/RUNX1可提高miR-181a-1的水平。我们进一步表明，miR-181a（miR-181a-1的功能对应物）可靶向ETV6/RUNX1，导致癌蛋白ETV6/RUNX1水平降低、细胞生长停滞、凋亡增加以及ETV6/RUNX1阳性细胞系中细胞分化的诱导。此外，miR-181a的异位表达还导致ETV6/RUNX1阳性原发性患者样本中CD10的过度表达降低。综上所述，我们的结果表明MIR181A1和ETV6/RUNX1相互调控，并且我们提出涉及MIR181A1和ETV6/RUNX1的双负反馈环可能导致ETV6/RUNX1驱动的pre-B ALL分化停滞。
