A Double Negative Loop Comprising ETV6/RUNX1 and MIR181A1 Contributes to Differentiation Block in t(12;21)-Positive Acute Lymphoblastic Leukemia

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

doi:10.1371/journal.pone.0142863

A Double Negative Loop Comprising ETV6/RUNX1 and MIR181A1 Contributes to Differentiation Block in t(12;21)-Positive Acute Lymphoblastic Leukemia

PLoS One. 2015 Nov 18;10(11):e0142863. doi: 10.1371/journal.pone.0142863. eCollection 2015.

Authors

Yung-Li Yang^{1

2}, Ching-Tzu Yen³, Chen-Hsueh Pai³, Hsuan-Yu Chen⁴, Sung-Liang Yu³, Chien-Yu Lin⁴, Chung-Yi Hu³, Shiann-Tarng Jou², Dong-Tsamn Lin^{1

2}, Shu-Rung Lin^{5

6}, Shu-Wha Lin³

Affiliations

¹ Departments of Laboratory Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.
² Departments of Pediatrics, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.
³ Departments of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan.
⁴ Institute of Statistical Science, Academia Sinica, Taipei, Taiwan.
⁵ Department of Bioscience Technology, College of Science, Chung-Yuan Christian University, Taoyuan, Taiwan.
⁶ Center for Nanotechnology and Center for Biomedical Technology, College of Science, Chung-Yuan Christian University, Taoyuan, Taiwan.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Differentiation / genetics
Cell Line, Tumor
Cell Proliferation
Core Binding Factor Alpha 2 Subunit / biosynthesis
Core Binding Factor Alpha 2 Subunit / genetics*
Core Binding Factor Alpha 2 Subunit / metabolism
ETS Translocation Variant 6 Protein
Gene Expression Regulation, Leukemic
Gene Knockdown Techniques
Humans
MicroRNAs / biosynthesis
MicroRNAs / genetics*
MicroRNAs / metabolism
Oncogene Proteins, Fusion / biosynthesis
Oncogene Proteins, Fusion / genetics
Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics*
Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology
Proto-Oncogene Proteins c-ets / biosynthesis
Proto-Oncogene Proteins c-ets / genetics*
Proto-Oncogene Proteins c-ets / metabolism
Repressor Proteins / biosynthesis
Repressor Proteins / genetics*
Repressor Proteins / metabolism
Translocation, Genetic / genetics*

Substances

Core Binding Factor Alpha 2 Subunit
MIrn181 microRNA, human
MicroRNAs
Oncogene Proteins, Fusion
Proto-Oncogene Proteins c-ets
RUNX1 protein, human
Repressor Proteins

Grants and funding

This work was supported by grants from the National Science Council of Taiwan, www.most.gov.tw/ (Grant No. NSC 102-2320-B-002-028-MY3, NSC 99-2314-B-002-016-MY3, NSC 100-2632-M-033-001-MY3, NSC 101-2632-M-033-001-MY2, NSC 102-2632-M-033-001-MY3, and NSC 102-2320-B-033 -003). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.