Menendez-Gutierrez, Maria PiedadPorcuna, JesusNayak, Ramesh CParedes, AnaNiu, HaixiaNunez, VanessaParanjpe, AditiGómez, MJBhattacharjee, AnukanaSchnell, Daniel JSanchez-Cabo, FatimaWelch JSSalomonis, NathanCancelas, JARicote, Mercedes2022-11-152022-11-152022-11-08Blood . 2022 Nov 8.http://hdl.handle.net/20.500.12105/15157Hematopoietic stem cells (HSCs) balance self-renewal and differentiation to maintain hematopoietic fitness throughout life. In steady-state conditions, HSC exhaustion is prevented by the maintenance of most HSCs in a quiescent state, with cells entering the cell cycle only occasionally. HSC quiescence is regulated by retinoid and fatty-acid ligands of transcriptional factors of the nuclear retinoid X receptor (RXR) family. Here, we show that dual deficiency for hematopoietic RXRa and RXRb induces HSC exhaustion, myeloid cell/megakaryocyte differentiation, and myeloproliferative-like disease. RXRa and RXRb maintain HSC quiescence, survival, and chromatin compaction; moreover, transcriptome changes in RXRa;RXRb-deficient HSCs include premature acquisition of an aging-like HSC signature, MYC pathway upregulation, and RNA intron retention. Fitness loss and associated RNA transcriptome and splicing alterations in RXRa;RXRb-deficient HSCs are prevented by Myc haploinsufficiency. Our study reveals the critical importance of RXRs for the maintenance of HSC fitness and their protection from premature aging.engVoRhttp://creativecommons.org/licenses/by/4.0/Atribución 4.0 Internacional3634701410.1182/blood.20220168321528-0020Bloodopen access