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Leukemia. 2019 May;33(5):1090-1101. doi: 10.1038/s41375-018-0301-z. Epub 2018 Dec 5.

Depletion of Ars2 inhibits cell proliferation and leukemogenesis in acute myeloid leukemia by modulating the miR-6734-3p/p27 axis.

Author information

1
College of Pharmacy, Army Medical University, Chongqing, China.
2
Department of Hematology, Southwest Hospital, Army Medical University, Chongqing, China.
3
Greater Philadelphia Pharmacy, Philadelphia, PA, USA.
4
Department of Hematology, Southwest Hospital, Army Medical University, Chongqing, China. chenjpxn@163.com.
5
College of Pharmacy, Army Medical University, Chongqing, China. gaoning59@163.com.
6
Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, China. gaoning59@163.com.

Abstract

Ars2 is a component of the nuclear cap-binding complex (CBC) that contributes to microRNA biogenesis and is required for cellular proliferation. Little is known regarding the functional role of Ars2 in cell proliferation and leukemogenesis of acute myeloid leukemia. Here, we show that the elevated expression of Ars2 was observed in acute myeloid leukemia (AML) cell lines and bone marrow samples from AML patients and was correlated with poorer overall survival. Overexpression of Ars2 promoted cell proliferation and colony formation in AML cells, whereas depletion of Ars2 inhibited cell proliferation and colony formation. Mechanistic studies reveal that depletion of Ars2 suppressed the interaction of Ars2 with CBC and led to alterations in miRNA processing. Furthermore, Ars2 depletion reduced the levels of miR-6734-3p, resulting in upregulation of p27 and culminating in cell cycle arrest at the G1 phase. In vivo studies indicate that depletion of Ars2 significantly reduced leukemic cell burden and prolonged the survival time of the leukemia-bearing mice. These findings indicate that Ars2 may not only play a crucial role in the regulation of cell proliferation and leukemogenesis, but could also be identified as a critical therapeutic target for treatment of AML.

PMID:
30518811
DOI:
10.1038/s41375-018-0301-z

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