Rora Regulates Hematopoietic Stem Cell Phenotypes and Progression of Chronic Myelogenous Leukemia.

Hematopoietic stem cell (HSC) aging leads to hematological dysfunction and diseases, but the regulatory factors involved remain incompletely characterized. In this study, the HSC Aging-Associated TFs Catalog System model was developed to identify transcription factors (TFs) that resist HSC aging. This approach revealed RAR-related orphan nuclear receptor alpha (RORA) as a key aging-negative-associated TF. Rora deletion in HSCs caused aged phenomes and functionally impaired their reconstitutive capacity. Additionally, Rora deficiency impaired leukemia stem cell proliferation and prevented chronic myelogenous leukemia. These findings establish RORA as a critical regulator in maintaining HSC function and provide insights into its therapeutic potential in hematological disorders.