CDK4-driven ketogenesis rewires histone modification to promote leukemia

Ketogenic nutrition has shown promise as an adjunct to conventional cancer therapies, its efficacy varies across cancer types depending on their metabolic characteristics.1,2 How ketogenic metabolites affect tumorigenesis, and whether ketone metabolism becomes deregulated in cancer cells, remain incompletely understood. Using T-cell acute lymphoblastic leukemia (T-ALL) as a model, we demonstrate that the ketone body ß-hydroxybutyrate (BHB) is elevated in cancer cells and exerts a strong pro-leukemogenic effect. Remarkably, the key ketogenic enzyme ß-hydroxybutyrate dehydrogenase 1 (BDH1) is significantly upregulated, enabling carbohydrate-driven BHB synthesis in leukemia cells. Mechanistically, aberrant CDK4 activation enables direct phosphorylation of BDH1 and enhances its protein stability. BDH1-mediated production of BHB augments histone ß-hydroxybutyrylation (Kbhb) and activates transcription of pro-leukemogenic genes. Either BDH1 deficiency or CDK4 inactivation significantly suppresses T-ALL progression in vivo. Notably, ketogenic diet markedly reduces the anti-leukemic efficacy of the clinically approved CDK4/6 inhibitor palbociclib. Together, these findings highlight how oncogenic CDK4 drives cancer cell ketogenesis through BDH1 phosphorylation and promotes tumor progression via an epigenetic mechanism. Moreover, the implementation of ketogenic nutrition in cancer therapy should be approached with caution and guided by the molecular pathogenesis of individual cancer types. Overall design: Fragmentation of the genome of Jurkat was achieved using ultrasonication, followed by immunoprecipitation with H3K9bhb and H3K9ac antibodies