Open AccessA Double Negative Loop Comprising ETV6/RUNX1 and MIR181A1 Contributes to Differentiation Block in t(12;21)-Positive Acute Lymphoblastic Leukemia
Author(s) -
YungLi Yang,
Chun-Wan Yen,
ChenHsueh Pai,
HsuanYu Chen,
SungLiang Yu,
ChienYu Lin,
Chung-Yi Hu,
Shiann-Tarng Jou,
DongTsamn Lin,
ShuRung Lin,
ShuWha Lin
Publication year - 2015
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0142863
Subject(s) - etv6 , runx1 , cancer research , biology , microrna , gene knockdown , fusion gene , microbiology and biotechnology , apoptosis , chromosomal translocation , transcription factor , gene , genetics
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.