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Methylation-mediated repression of microRNA-143 enhances MLL–AF4 oncogene expression

Oncogene volume 31, pages 507–517 (2012)Cite this article

Abstract

Fusion proteins containing the amino terminus of mixed lineage leukemia (MLL) are common in acute lymphoblastic leukemia (ALL) due to translocations. The MLL–AF4 fusion protein is generated by the translocation t(4;11)(q21;q23), and t(4;11)-positive ALL patients (MLL–AF4 ALL), have a notoriously poorer prognosis compared with patients with other MLL-associated leukemias. The detailed role of this fusion protein in leukemogenesis is not well understood. MicroRNAs (miRNAs) targeting the AF4 3′ untranslated regions may modulate MLL–AF4 fusion protein levels, raising the question of whether regulation of these miRNAs are involved in the progression of MLL–AF4 ALL. In this study, we show that miR-143 was identified as a regulator of MLL–AF4 expression in MLL–AF4 ALL samples. Restoration of miR-143 in MLL–AF4-positive RS4;11 and MV4-11 cells induced apoptosis, negatively contributing to leukemia cell growth by reducing MLL–AF4 fusion protein levels. Furthermore, miR-143 was epigenetically repressed by promoter hypermethylation in MLL–AF4-positive primary blasts and cell lines, but not in normal bone marrow cells and MLL–AF4-negative primary blasts, which was directly associated with expression of the MLL–AF4 oncogene. This is the first study to show that miR-143 functions as a tumor suppressor in MLL–AF4 B-cell ALL. These data reveal the therapeutic promise of upregulating miR-143 expression for MLL–AF4 B-cell ALL.

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Acknowledgements

We are grateful to Professor Xiaofei Zheng for miRNA-expressing plasmids. We thank Wei Wang, Yi Ding, Yuanyuan Xu, Nan Wang, Chengwang Xu, Meng Li, Xufeng Luo, Huiyuan Kang, Xinrong Wang and Xiaoning Gao for excellent technical assistance. This work was supported by the National Natural Science Foundation of China (Nos. 30800482, 30971297 and 90919044), Medical Capital Development Fund (2007-2040), the Beijing Natural Science Foundation of China (No. 7102147) and the National 973 Project of China (No. 2005CB522400).

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  1. L Dou, D Zheng and J Li: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Hematology, Chinese PLA General Hospital, Beijing, China

    L Dou, J Li, Y Li, L Gao, L Wang & L Yu

  2. Department of Hepatobiliary Surgery, Organ Transplant Center, Chinese PLA 309th Hospital, Beijing, China

    D Zheng

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  1. L Dou
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Correspondence to L Wang or L Yu.

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Dou, L., Zheng, D., Li, J. et al. Methylation-mediated repression of microRNA-143 enhances MLL–AF4 oncogene expression. Oncogene 31, 507–517 (2012). https://doi.org/10.1038/onc.2011.248

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