The retinoic acid receptor transcriptional coregulator RIP140 predicts poor outcome and restrains ATRA response in acute myeloid leukemia

Despite advances in acute myeloid leukemia (AML) therapy, overall survival remains poor except in acute promyelocytic leukemia (APL), where all-trans retinoic acid (ATRA) dramatically improved outcomes. However, ATRA showed limited efficacy in non-APL AML, highlighting the need for biomarkers to identify differentiation-responsive patients. Here, we demonstrated that the transcriptional coregulator RIP140 was upregulated in hematopoietic stem cells, immature AML blasts, and at relapse, and acted as a poor prognostic factor across most AML subtypes except APL, where high expression was associated with a better predicts ATRA response. RNA-seq analysis in RIP140-silenced MOLM14 cells revealed that RIP140 did not block ATRA-induced myeloid differentiation but redirected it: in RIP140-expressing cells, ATRA enhanced immune cell activation and mitochondrial metabolism while it repressed cell-cycle and DNA replication/repair pathways. RIP140 silencing enhanced ATRA effect on chromatin, transcription and macromolecules biosynthesis, whereas RIP140 shifted ATRA inhibitory effects toward translational control and ubiquitin-proteasome-mediated protein degradation. Consistent with this transcriptional reprogramming, RIP140 knockdown enhanced ATRA-induced differentiation, apoptosis, and proliferation arrest. These findings position RIP140 as a novel biomarker and potential therapeutic target to optimize ATRA responsiveness in non-APL AML patients.