Dissecting the role of microRNAs in acute myeloid leukaemic stem cells

Acute myeloid leukaemia (AML) remains a deadly disease for children, with poor survival and high relapse rates. The occurrence of relapse is mainly attributed to the persistence of leukaemic stem cells (LSCs), which possess self-renewal and proliferative ability and contribute to the initiation and maintenance of leukaemia. Current efforts have been done on developing therapeutic strategies targeting LSCs. microRNAs (miRNAs), which are commonly dysregulated in cancer, have been identified as promising targets for cancer treatment. Although miRNAs have been implicated in regulating cancer stem cells, only a few studies have focused on exploring the function of tumour suppressor miRNAs in LSCs. This study identified dysregulated miRNAs and investigated their role in regulating genes and epigenetic pathways activated in AML LSCs. By performing miRNA microarray analysis, this study identified a novel tumour suppressor, miR-101a, that is downregulated in mixed-lineage leukaemia (MLL) pre-LSCs (an early developmental stage of LSCs) derived from haematopoietic stem cells (HSCs). Overexpression of miR-101a in pre-LSCs inhibited clonogenic growth and cell proliferation in vitro and significantly delayed onset of MLL-mediated AML in mice. The impaired proliferative ability of miR-101a transduced cells was associated with apoptotic induction and inhibition of G1-to-S phase transition. Results of this study also revealed a significant reduction in enhancer of zeste homologue 2 (EZH2), a known target of miR-101a and a crucial epigenetic regulator in the maintenance of MLL-rearranged AML, which was accompanied by a global decrease of histone methylation changes, H3K27Me3, H3K36Me2, and H3K79Me2. Gene expression profiling also identified miR-101a as a potential regulator of cell cycle (e.g. p21CIP1/WAF1), self-renewal genes (e.g. TCF7L2 and MEIS1A), and glycolysis enzyme (i.e. Pgk1). Data obtained from this study also revealed that overexpression of miR-101a only influenced the gene signature from HSC-derived MLL leukaemic cells but had no effect on that from progenitor-derived MLL leukaemic cells, suggesting a cell-of-origin dependent effect. Collectively, re-expression of miR-101a in MLL pre-LSCs reverses the epigenetic landscape and altered genes/pathways essential for LSC function, thereby impairing leukaemogenesis. Targeting miR-101a may be a promising therapeutic strategy for AML