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MicroRNA gene expression during retinoic acid-induced differentiation of human acute promyelocytic leukemia

A Correction to this article was published on 11 May 2022

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MicroRNAs (miRNAs) are small non-coding RNAs of 19–25 nucleotides that are involved in the regulation of critical cell processes such as apoptosis, cell proliferation and differentiation. However, little is known about the role of miRNAs in granulopoiesis. Here, we report the expression of miRNAs in acute promyelocytic leukemia patients and cell lines during all-trans-retinoic acid (ATRA) treatment by using a miRNA microarrays platform and quantitative real time–polymerase chain reaction (qRT–PCR). We found upregulation of miR-15a, miR-15b, miR-16-1, let-7a-3, let-7c, let-7d, miR-223, miR-342 and miR-107, whereas miR-181b was downregulated. Among the upregulated miRNAs, miR-107 is predicted to target NFI-A, a gene that has been involved in a regulatory loop involving miR-223 and C/EBPa during granulocytic differentiation. Indeed, we have confirmed that miR-107 targets NF1-A. To get insights about ATRA regulation of miRNAs, we searched for ATRA-modulated transcription factors binding sites in the upstream genomic region of the let-7a-3/let-7b cluster and identified several putative nuclear factor-kappa B (NF-κB) consensus elements. The use of reporter gene assays, chromatin immunoprecipitation and site-directed mutagenesis revealed that one proximal NFB binding site is essential for the transactivation of the let-7a-3/let-7b cluster. Finally, we show that ATRA downregulation of RAS and Bcl2 correlate with the activation of known miRNA regulators of those proteins, let-7a and miR-15a/miR-16-1, respectively.

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This work was supported by National Cancer Institute/National Institutes of Health Grants, P01CA76259, P01CA16058 and P01CA81534 (CMC), P01 CA055164 and the Paul and Mary Haas Chair in Genetics (MA), Lauri Strauss Discovery grants awards (RG), Kimmel Foundation grants awards (GAC and RA) and CLL Global Research Foundation Grant (GAC). We thank Guido Marcucci for kindly providing us with NB4 cells and Dennis Guttridge for his generous support with many reagents used to characterize the NFB regulated miRNAs (The Ohio State University).

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Correspondence to C M Croce.

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Garzon, R., Pichiorri, F., Palumbo, T. et al. MicroRNA gene expression during retinoic acid-induced differentiation of human acute promyelocytic leukemia. Oncogene 26, 4148–4157 (2007).

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