miR-638 regulates differentiation and proliferation in leukemic cells by targeting cyclin-dependent kinase 2.

Abstract

MicroRNAs have been extensively studied as regulators of hematopoiesis and leukemogenesis. We identified miR-638 as a novel regulator in myeloid differentiation and proliferation of leukemic cells. We found that miR-638 was developmentally up-regulated in cells of myeloid but not lymphoid lineage. Furthermore, significant miR-638 down-regulation was observed in primary acute myeloid leukemia (AML) blasts, whereas miR-638 expression was dramatically up-regulated in primary AML blasts and leukemic cell lines undergoing forced myeloid differentiation. These observations suggest that miR-638 might play a role in myeloid differentiation, and its dysregulation may contribute to leukemogenesis. Indeed, ectopic expression of miR-638 promoted phorbol 12-myristate 13-acetate- or all-trans-retinoic acid-induced differentiation of leukemic cell lines and primary AML blasts, whereas miR-638 inhibition caused an opposite phenotype. Consistently, miR-638 overexpression induced G1 cell cycle arrest and reduced colony formation in soft agar. Cyclin-dependent kinase 2 (CDK2) was found to be a target gene of miR-638. CDK2 inhibition phenotypically mimicked the overexpression of miR-638. Moreover, forced expression of CDK2 restored the proliferation and the colony-forming ability inhibited by miR-638. Our data suggest that miR-638 regulates proliferation and myeloid differentiation by targeting CDK2 and may serve as a novel target for leukemia therapy or marker for AML diagnosis and prognosis.

• Authors: Yi Lin, Dengju Li, Qing Liang, Shangqing Liu, Xuelan Zuo, Lin Li, Xuemei Sun, Wenxin Li, Mingxiong Guo, Zan Huang
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 290 Issue 3 Pg. 1818-28 (Jan 16 2015) ISSN: 1083-351X [Electronic] United States
• PMID: 25451924 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• Biomarkers, Tumor
• MIRN638 microRNA, human
• MicroRNAs
• Oligonucleotides
• CDK2 protein, human
• Cyclin-Dependent Kinase 2
• Tetradecanoylphorbol Acetate

Topics

• Base Sequence
• Biomarkers, Tumor (metabolism)
• Cell Differentiation
• Cell Line, Tumor
• Cell Proliferation
• Cyclin-Dependent Kinase 2 (genetics, metabolism)
• Gene Expression Regulation, Leukemic
• HEK293 Cells
• HL-60 Cells
• Hematopoiesis
• Humans
• Leukemia, Myeloid, Acute (metabolism)
• MicroRNAs (genetics, metabolism)
• Molecular Sequence Data
• Oligonucleotides (genetics)
• Phenotype
• Sequence Homology, Nucleic Acid
• Tetradecanoylphorbol Acetate
• Up-Regulation