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

Abstract

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.

Metabolic reprogramming involves in transition of activated/resting CD4+ memory T cells and prognosis of gastric cancer

“…Vitamin-like A is a retinol derivative that is necessary for epithelial differentiation and healthy embryonic development ( 54 ). ATRA, a biologically active metabolite of vitamin-like A, has shown significant promise in various malignancies, including epithelial carcinoma, precancerous lesions, and acute promyelocytic leukemia (APL) ( 55 ). The compound has been used in chemoprevention and differentiation therapy for several cancers, and has shown good efficacy in combination with pembrolizumab for metastatic melanoma ( 56 ).…”

All-trans retinoic acid in hematologic disorders: not just acute promyelocytic leukemia

“…An inhibitor of MEK, trametinib, in combination with ATRA restored the sensitivity of ATRA-resistant AML cell lines to ATRA by enhancing the protein levels of STAT3 and phosphorylation of Akt or JNK, and STAT3, PI3K, and JNK inhibitors all inhibited trametinib + ATRA induced cell differentiation in AML cell lines ( Lu et al, 2021 ). ATRA inhibits translation and protein synthesis in AML cells, and the genes regulated by ATRA are mainly concentrated in the PI3K/AKT signaling pathway, and ATRA + PI3K/AKT inhibitor induces a large number of apoptotic cells and greatly inhibits cloning of AML cells ( Wang K. et al, 2022 ). ATRA treatment of differentiation-responsive AML cells induces persistent inhibition of BCL-2, while first upregulating and then decreasing the level of MCL-1.…”