MiR-181a enhances drug sensitivity of mixed lineage leukemia-rearranged acute myeloid leukemia by increasing poly(ADP-ribose) polymerase1 acetylation

Abstract

Chromosomal translocations and rearrangements involving Mixed Lineage Leukemia (MLL) gene is associated with poor prognosis in AML. Extensive epigenetic changes were found in this group of patients. In clinical study, we found miR-181a expression level was significantly lower in MLL-rearranged AML. As an important epi-miRNA, the role of miR-181a as an epigenetic regulator in leukemia has not been investigated before. In this study, we found miR-181a overexpression enhanced total protein acetylation in THP-1 cells, which harbor MLL-AF9 fusion gene, and protein Mass Spectrum identified poly(ADP-ribose) polymerase 1 (PARP1) was a major downstream target. Increased PARP1 acetylation was mediated by down-regulation of histone deacetylase Sirtuin1 (Sirt1). MiR-181a overexpression resulted in DNA trapping of PARP1, increased DNA double strand break formation and increased chemosensitivity of leukemia cells both in vitro and in vivo. This study indicates miR-181a-Sirt1-PARP1 acetylation pathway could be a promising target for this special group of AML.

Keywords:

• PARP1
• acetylation
• miR-181a
• Sirt1
• AML

Acknowledgements

We would like to express our gratitude to all the stuff in the Department of Hematology of Drum Tower Hospital. They offered great help and useful suggestions when we prepared this manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

The work was supported by National Natural Science Foundation of China [grant number 81370683].