MiR-181a enhances drug sensitivity of mixed lineage leukemia-rearranged acute myeloid leukemia by increasing poly(ADP-ribose) polymerase1 acetylation. Issue 1 (2nd January 2021)

• Record Type: Journal Article
• Authors: Zhou, Di; Xu, Peipei; Zhou, Xuan; Diao, Zhenyu; Ouyang, Jian; Yan, Guijun; Chen, Bing
• Is Part Of: Leukemia & lymphoma. Volume 62:Issue 1(2021)
• Page Start: 136
• Page End: 146
• Publication Date: 2021-01-02
• Subjects: PARP1 -- acetylation -- miR-181a -- Sirt1 -- AML; Leukemia -- Periodicals; Lymphomas -- Periodicals; 616.99419
• DOI: 10.1080/10428194.2020.1824067
• Languages: English
• ISSNs: 1042-8194

Abstract

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.