Ketogenic regulation of histone modification by CDK4 promotes leukemogenesis [RNA-seq]

While ketogenic nutrition shows promise as an adjunct to conventional cancer therapies, its efficacy varies depending on the type of cancer and its specific metabolic characteristics. How ketone bodies affect tumorigenesis and how the ketogenic pathway becomes deregulated in cancer remain to be fully understood. Using T-cell acute lymphoblastic leukemia (T-ALL) as a model, we here demonstrate that ketogenic metabolite β-hydroxybutyrate (BHB) plays a remarkable pro-leukemogenic role in mice. T-ALL cells generally exhibited greater expression of β-hydroxybutyrate dehydrogenase (BDH1), the metabolic enzyme that leads to cell autonomous synthesis of BHB. Mechanistically, aberrant CDK4 activation enables direct phosphorylation of BDH1 at the serine 296 residue and enhances its protein stability. Importantly, BDH1 deficiency leads to robust growth inhibition and cell death of human T-ALL cells, and markedly impedes NOTCH1-induced T-ALL progression in mice. BDH1-mediated production of BHB enhances the histone modification of β-hydroxybutyrylation (Kbhb), thereby leading to transcriptional activation of pro-leukemogenic genes MYC and NKX3.1. These findings shed light on how oncogenic CDK4 deregulates ketogenesis and promotes leukemia progression via an epigenetic mechanism. Therefore, ketogenic diets or ketone supplements should be taken with caution by cancer patients. Therapeutic interventions targeting key ketogenic enzymes may hold great promise for leukemia treatment.