GAS6-AS1/YBX1/MYC oncogenic axis promotes cell propagation and disease progression of acute myeloid leukemia

Developing new molecularly targeted therapies to improve the prognosis of acute myeloid leukemia (AML) is greatly needed. The oncogenic transcription factor MYC is an attractive target for leukemia therapeutics due to its regulation by multiple, converging signaling cascades. However, limited knowledge is known about the underlying mechanism by which MYC dysregulation was conducted. Long noncoding RNAs (lncRNAs) are known to play a key role in acute myeloid leukemia (AML) initiation and progression. In this study, we aim to identify the involvement of the lncRNA in MYC-driven leukemia proliferation and progression. By integrated bioinformatics analysis, we identified GAS6-AS1 as a significantly differentially expressed gene, which was further proved to be an oncogenic lncRNA associated with poor prognosis of AML. Mechanically, RNA-binding proteins (RBPs) are critical regulators of transcription and translation that are often dysregulated in cancer. Y-box binding protein 1 (YBX1) is a versatile RNA-binding protein with a variety of interacting partners. We revealed that GAS6-AS1 binds YBX1 to facilitate its interaction with MYC, leading to transactivation of MYC and upregulation of IL1R1 and other MYC target genes associated with leukemia progression. Lentiviral-based in vivo knockdown of GAS6-AS1 exhibits a promising prospect in AML treatment. These results indicate that therapeutic targeting of the GAS6-AS1/YBX1/MYC axis inhibits AML cellular propagation and disease progression.