The Translational Landscape Revealed the Sequential Treatment Containing ATRA plus PI3K/AKT Inhibitors as an Efficient Strategy for AML Therapy

The present study aimed to better understand the possibility of utilizing all-trans retinoic acids (ATRA) in acute myeloid leukemia (AML). We found that ATRA significantly suppressed global translation and protein synthesis in AML cells. The efficacy of ATRA in treating AML required its translational regulatory functions, as shown by the fact that the decrease in the universal eukaryotic initiation factor 4E (eIF4E) was essential to maintain the induction of cell growth arrest and differentiation by ATRA. By establishing a specific translational landscape, we suggested that transcripts with simple 5′UTR gained a translational advantage in AML cells during ATRA stress. Based on that, the genes translationally regulated by ATRA were mainly enriched in phosphatidylinositol-3-kinase/Akt (PI3K/AKT) signaling; we subsequently revealed that PI3K/AKT activation was required for ATRA to effectively induce AML cell differentiation. However, PI3K/AKT has been reported to promote the stemness of AML cells. As such, we further suggested that sequential treatment including ATRA and PI3K/AKT inhibitor induced robust apoptosis, extremely inhibited the clonality of AML cells, and suppressed the FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD)-driven transformation of CD34(+) hematopoietic stem/progenitor cells. Future clinical studies are warranted to further support the clinical application of the sequential strategy for the effective treatment of AML.