Abstract 1917: Suppression of miR-101a contributes to leukemogenesis by regulating epigenetic and pro-survival pathways in MLL AML stem cells
2016
The occurrence of relapse in acute myeloid leukemia (AML) is attributed to the persistence of leukemic stem cells (LSCs), which possess self-renewal and proliferative ability and contributes to the initiation and maintenance of leukemia (Nature 2001, 414:105-111). LSCs are also inherently drug-resistant (Oncotarget 2010, 1: 552-566). Recently, microRNAs (miRNAs), a class of small noncoding RNAs, have been implicated in regulation of cancer stem cells (CSCs). Several studies have shown that depletion of miRNAs leads to cancer and miRNA overexpression represents a promising strategy for cancer treatment (Nature Rev. 2010, 9: 775-789). Our study aims to develop an LSC-targeted therapeutic strategy by identifying miRNAs regulating gene and epigenetic pathways activated in Mixed-Lineage Leukemia (MLL)-mediated AML stem cells. We performed miRNA microarray analysis of MLL-AF9 mediated pre-leukemic stem cells (pre-LSCs) compared to Hoxa9/Meis1a-derived pre-LSCs and identified a novel tumor suppressor, miR-101a, that is downregulated in MLL-AF9 pre-LSCs (P 1.25). Quantitative real-time PCR confirmed the results and further analysis revealed that miR-101a is suppressed in LSCs compared to normal hematopoietic stem cells, suggesting a tumor suppressor role of miR-101a. Serial replating assay showed that overexpressing miR-101a in MLL-AF9 pre-LSCs impaired proliferation as we have observed 60-70% reduction in cell and colony number (p Our data show that miR-101a is supressed in MLL AML stem cells and its forced expression impairs LSC functions via reversing the epigenetic landscape and inhibiting pro-survival pathways, leading to apoptotic cell death. Overexpression of miR-101a may provide a means to eradicate drug-resistant LSCs. Citation Format: Estrella Gonzales-Aloy, Murray D. Norris, Jenny Y. Wang. Suppression of miR-101a contributes to leukemogenesis by regulating epigenetic and pro-survival pathways in MLL AML stem cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1917.
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