Retinoid X receptor promotes hematopoietic stem cell fitness and quiescence and preserves hematopoietic homeostasis

•RXRs are ligand-activated transcriptional units needed for the maintenance of HSC fitness, and preservation of a balanced hematopoiesis.•RXRα;RXRβ-deficient HSCs transition from a dormant to a transcriptionally and proliferative-active state through MYC pathway activation. [Display omitted] Hematopoietic 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. Herein, we show that dual deficiency for hematopoietic RXRα and RXRβ induces HSC exhaustion, myeloid cell/megakaryocyte differentiation, and myeloproliferative-like disease. RXRα and RXRβ maintain HSC quiescence, survival, and chromatin compaction; moreover, transcriptome changes in RXRα;RXRβ-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 RXRα;RXRβ-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. Retinoids and their family of receptors play a role in the maintenance of quiescent hematopoietic stem cells (HSCs). Analyses of retinoid X receptor (RXR) conditional knockout mice by Menéndez-Gutiérrez and colleagues identifies MYC pathway activation in RXR-deficient HSCs. This leads to a decreased quiescent HSC pool, stem cell exhaustion, myeloid cell/megakaryocyte differentiation, and myeloproliferative-like disease.