Induction of microRNAs, mir-155, mir-222, mir-424 and mir-503, promotes monocytic differentiation through combinatorial regulation

Abstract

Acute myeloid leukemia (AML) involves a block in terminal differentiation of the myeloid lineage and uncontrolled proliferation of a progenitor state. Using phorbol myristate acetate (PMA), it is possible to overcome this block in THP-1 cells (an M5-AML containing the MLL-MLLT3 fusion), resulting in differentiation to an adherent monocytic phenotype. As part of FANTOM4, we used microarrays to identify 23 microRNAs that are regulated by PMA. We identify four PMA-induced microRNAs (mir-155, mir-222, mir-424 and mir-503) that when overexpressed cause cell-cycle arrest and partial differentiation and when used in combination induce additional changes not seen by any individual microRNA. We further characterize these prodifferentiative microRNAs and show that mir-155 and mir-222 induce G2 arrest and apoptosis, respectively. We find mir-424 and mir-503 are derived from a polycistronic precursor mir-424-503 that is under repression by the MLL-MLLT3 leukemogenic fusion. Both of these microRNAs directly target cell-cycle regulators and induce G1 cell-cycle arrest when overexpressed in THP-1. We also find that the pro-differentiative mir-424 and mir-503 downregulate the anti-differentiative mir-9 by targeting a site in its primary transcript. Our study highlights the combinatorial effects of multiple microRNAs within cellular systems.

Hypermethylation of specific microRNA genes in MLL-rearranged infant acute lymphoblastic leukemia: major matters at a micro scale

“…In t(9;11)-positive myeloid leukemias, miR-424 expression was repressed by the MLL-AF9 fusion protein. 34 In this study, we show that the miR-424-503 cluster is downregulated by CpG island hypermethylation in t(4;11)-positive ALL, possibly directed by the MLL-AF4 fusion. Likewise, miR-10a is downregulated in MLL-rearranged acute myeloid leukemia.…”

Mouse miRNA-709 directly regulates miRNA-15a/16-1 biogenesis at the posttranscriptional level in the nucleus: evidence for a microRNA hierarchy system

“…This supervision, in turn, constitutes a short-term regulatory cascade with a quick response to apoptotic stress independent of any neo transcription. To the best of our knowledge, this is the first report on the direct miRNA-mediated regulation of biogenesis and function of miRNAs although previous studies have shown inter-miRNA antagonisms [20,21] and protein-mediated post-transcriptional control in miR-NA biogenesis [22][23][24]. Interestingly, Tamminga et al [19] showed that the in situ hybridization signal of miR-709 is predominately located in the nucleus.…”

The role of miR-29 family members in malignant hematopoiesis

“…MiR-155 was up-regulated in FLT3-ITD positive adult AML (ref. 91 ), down-regulation of miR-196a/b was found in adult MLL rearranged AML (ref. 92 ) and over-expression of miR-181 was associated with a high percentage of blasts in AML with a favorable outcome 93 .…”