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

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.