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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE270919 | GEO | 2025/12/09

REPOSITORIES: GEO

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Project description:In Alzheimer’s disease, dysfunctional microglia possess abnormal immunometabolic features that cause neuronal/synaptic damage and aggravate pathology. A critical question is how to reverse or fine-tune abnormal microglial metabolism towards beneficial immunometabolic outcomes. A major metabolic intervention strategy to raise circulating ketone levels for health benefits, such as by consumption of a ketogenic diet 1, fasting, or other approaches collectively called ketotherapeutics, has raised a great deal of interest, but its effects on microglia are not well understood. Our previous in vitro study showed that β-hydroxybutyrate (BHB), a major ketone body, reverses multiple pathological features of amyloid-β oligomer (AβO)-activated human microglia. In the current study, we tested the in vivo effects of BHB on microglia and synaptic plasticity in the 5xFAD Alzheimer’s disease mouse model. To capture the metabolic impact of BHB on microglia, we employed a “subacute” 1-week regimen of daily intraperitoneal injection of BHB (250 mg/kg), which induced brief and mild episodic (daily) ketosis. This short regimen was able to mitigate pro-inflammatory microglia activation linked to NLRP3 inflammasome formation, and reduce brain amyloid-β deposition by enhancing phagocytosis. Remarkably, this regimen mitigated the deficits of hippocampal long-term depression but not long-term potentiation, and this effect was linked to suppression of the inflammasome-generated cytokine IL-1β. Our results suggest that short-term BHB treatment may ameliorate microglial abnormalities and microglia-regulated synaptic deficits in Alzheimer’s disease. Because beneficial results were achieved with mild episodic BHB elevation alone without diet restriction and without the need of feeding a KD, our results have significant implications to human ketotherapeutics. As KDs are known for poor compliance and low sustainability due to their restrictive nature, our study opens the possibility for alternative ketogenic approaches that are less restrictive, potentially safer, and easier for compliance than a KD, such as short-term BHB injections or dietary ketone esters, a translatable form of induced ketosis.

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

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