Regulation of gene expression at the RNA level is an important regulatory mechanism in cancers. However, post-transcriptional molecular pathways underlying tumorigenesis remain largely unexplored. In this study, we uncovered a functional axis consisting of microRNA (miR)-148a-3p, RNA helicase DDX6, and its downstream target TXNIP in Acute Myeloid Leukemia (AML). Using a DROSHA-knockout cell system to evaluate miR-mediated gene expression control, we comprehensively profiled putative transcripts regulated by miR-148a-3p and identified DDX6 as a direct target of miR-148a-3p in AML cells. DDX6 depletion induced cell cycle arrest, apoptosis, and differentiation while delaying leukemia development in vivo. Genome-wide assessment of DDX6 binding transcripts and gene expression profiling of DDX6-depleted cells revealed TXNIP, a tumor suppressor, as the functional downstream target of DDX6. Overall, our study identified DDX6 as a post-transcriptional regulator that is required for AML survival. We proposed the regulatory link between miR-148a-3p and DDX6 as a potential therapeutic target in leukemia.

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