ERK promotes miR34a/ISOC1 signaling to enhance all trans retinoic acid-induced myeloid differentiation in acute promyelocytic leukemia.

While all-trans retinoic acid (ATRA) is successfully used to treat acute promyelocytic leukemia (APL), therapeutic resistance remains a major clinical challenge, highlighting an urgent need to identify the regulators of ATRA efficiency. In the present study, we analyzed paired bone marrow samples of patients with APL and found that miR34a isoforms (-3p and -5p) were significantly elevated at complete remission compared to initial diagnosis. Overexpression of pre-miR34a enhanced ATRA-induced myeloid differentiation in APL cells as well as in xenograft models. Mechanistically, we found that miR34a promoted G1/S cell cycle arrest and reduced the protein level of CDK6, a validated target of miR34a-5p. Furthermore, bioinformatic analysis predicted ISOC1 was a target of miR34a-3p, and dual-luciferase reporter assays validated the direct binding of miR34a-3p to the 3' UTR of ISOC1. Gene set enrichment analysis (GSEA) illustrated "hematopoietic cell lineage" pathway was significantly enriched in patients with acute myeloid leukemia (AML) having low levels of ISOC1. Knockdown of ISOC1 enhanced ATRA-induced myeloid differentiation, and rescue experiments confirmed that miR34a regulated ATRA efficiency by targeting ISOC1. Moreover, ERK inhibition blocked the ability of miR34a to enhance ATRA-induced myeloid differentiation. Consistently, ERK inactivation significantly reduced miR34a-3p levels while increased ISOC1 levels in the presence of ATRA. Taken together, Our findings demonstrated that miR34a enhanced ATRA-induced myeloid differentiation by targeting CDK6 via miR34a-5p and ISOC1 via miR34a-3p, ERK signaling promoted ATRA-induced myeloid differentiation through miR34a-3p/ISOC1 axis. Targeting this regulatory axis may provide a novel combinatorial strategy to improve the therapeutic efficacy of ATRA in APL.