Cytoplasmic DROSHA and non-canonical mechanisms of MiR-155 biogenesis in FLT3-ITD acute myeloid leukemia
- 15 February 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Leukemia
- Vol. 35 (8), 2285-2298
- https://doi.org/10.1038/s41375-021-01166-9
Abstract
We report here on a novel pro-leukemogenic role of FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) that interferes with microRNAs (miRNAs) biogenesis in acute myeloid leukemia (AML) blasts. We showed that FLT3-ITD interferes with the canonical biogenesis of intron-hosted miRNAs such as miR-126, by phosphorylating SPRED1 protein and inhibiting the “gatekeeper” Exportin 5 (XPO5)/RAN-GTP complex that regulates the nucleus-to-cytoplasm transport of pre-miRNAs for completion of maturation into mature miRNAs. Of note, despite the blockage of “canonical” miRNA biogenesis, miR-155 remains upregulated in FLT3-ITD+ AML blasts, suggesting activation of alternative mechanisms of miRNA biogenesis that circumvent the XPO5/RAN-GTP blockage. MiR-155, a BIC-155 long noncoding (lnc) RNA-hosted oncogenic miRNA, has previously been implicated in FLT3-ITD+ AML blast hyperproliferation. We showed that FLT3-ITD upregulates miR-155 by inhibiting DDX3X, a protein implicated in the splicing of lncRNAs, via p-AKT. Inhibition of DDX3X increases unspliced BIC-155 that is then shuttled by NXF1 from the nucleus to the cytoplasm, where it is processed into mature miR-155 by cytoplasmic DROSHA, thereby bypassing the XPO5/RAN-GTP blockage via “non-canonical” mechanisms of miRNA biogenesis.Funding Information
- U.S. Department of Health & Human Services | National Institutes of Health (CA205247, CA201184, CA205247, CA201184, CA205247, CA201184, CA205247, CA201184, P30CA033572)
- U.S. Department of Health & Human Services | National Institutes of Health
- U.S. Department of Health & Human Services | National Institutes of Health
- U.S. Department of Health & Human Services | National Institutes of Health
- U.S. Department of Health & Human Services | National Institutes of Health
- U.S. Department of Health & Human Services | National Institutes of Health
- U.S. Department of Health & Human Services | National Institutes of Health
- U.S. Department of Health & Human Services | National Institutes of Health
- Jerome Foundation (G.M.)
- U.S. Department of Health & Human Services | National Institutes of Health
This publication has 55 references indexed in Scilit:
- Genomic and Epigenomic Landscapes of Adult De Novo Acute Myeloid LeukemiaThe New England Journal of Medicine, 2013
- Attenuation of miR-126 Activity Expands HSC In Vivo without ExhaustionCell Stem Cell, 2012
- Sprouty-related Ena/Vasodilator-stimulated Phosphoprotein Homology 1-Domain-containing Protein (SPRED1), a Tyrosine-Protein Phosphatase Non-receptor Type 11 (SHP2) Substrate in the Ras/Extracellular Signal-regulated Kinase (ERK) PathwayOnline Journal of Public Health Informatics, 2011
- AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML)Blood, 2009
- In vivo delivery of siRNA to immune cells by conjugation to a TLR9 agonist enhances antitumor immune responsesNature Biotechnology, 2009
- Epstein–Barr virus latent membrane protein 1 trans-activates miR-155 transcription through the NF-κB pathwayNucleic Acids Research, 2008
- The Endothelial-Specific MicroRNA miR-126 Governs Vascular Integrity and AngiogenesisDevelopmental Cell, 2008
- Distinctive microRNA signature of acute myeloid leukemia bearing cytoplasmic mutated nucleophosminProceedings of the National Academy of Sciences of the United States of America, 2008
- Coordinated expression of microRNA-155 and predicted target genes in diffuse large B-cell lymphomaCancer Genetics and Cytogenetics, 2008
- Prediction of post‐translational glycosylation and phosphorylation of proteins from the amino acid sequenceProteomics, 2004