Ketogenic Regulation of Histone Modification By CDK4 Promotes Leukemogenesis

Ketogenic regulation of histone modification by CDK4 promotes leukemogenesis Jin Xu1,2#, Yinpeng Bai1,2#, Qilong Li1,2#, Jing Zuo2, Peipei Sun2, Hao Huang2, Ting Xie2, Mengjie Yang2, Xinlu Li2, Yuan Wang3, Guoliang Qing1,2, Hudan Liu1,2* 1Department of Hematology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China 2Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Wuhan University, Wuhan 430071, China 3Department of Physiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China #These authors contributed equally to this work. The authors declare no conflict of interest. T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive lymphoid tumor characterized by the diffuse infiltration of the bone marrow by malignant haematopoietic cells expressing immature T cell markers. In the past decade, high-dose multi-agent chemotherapy remains the mainstay treatment for T-ALL patients. However, a considerable number of patients experience disease relapse and develop resistance to standard clinical interventions, leading to a dismal survival rate. The molecular pathogenesis of T-ALL unveils a multistep transformation process wherein accumulating genetic alterations coordinate crucial oncogenic pathways. The loss of cell cycle control has a prominent role in the pathogenesis of T-ALL. The tumor suppressors p16INK4A and p14ARF encoded by the CDKN2A locus are deleted in most (>70%) T-ALL cases. The p16INK4A tumor suppressor directly binds to and inactivates cyclin D-CDK4 and cyclin D-CDK6 complexes. While these mutations do disrupt cell cycle regulation, the precise mechanisms by which hyperactive cell cycle kinases contribute to leukemogenesis remain incompletely understood. Cyclin-dependent kinases (CDKs) are serine/threonine kinases that control cell division and transcription in eukaryotes, dysregulation of which is a hallmark of cancer. It is well established that CDK4 phosphorylates and inactivates retinoblastoma tumor suppressor, promoting the cell-cycle during G1/S transition. Whether and how CDK4 engages in other cellular processes remains unclear. We here provide a unique link between CDK4 and ketogenesis in cancer cells. Using T-cell acute lymphoblastic leukemia (T-ALL) as a model system, we demonstrate that aberrant CDK4 activation in human cancer enables direct phosphorylation and stabilization of β-hydroxybutyrate dehydrogenase (BDH1), the metabolic enzyme responsible for synthesis of ketone body β-hydroxybutyrate (BHB). BDH1-mediated production of BHB enhances the histone modification of β-hydroxybutyrylation (Kbhb), thereby leading to transcriptional activation of pro-leukemogenic genes NKX3.1 and MYC. Functional investigation demonstrates the indispensable role of the CDK4-BDH1 axis in leukemogenesis in vivo. These findings emphasize the significance of cell cycle kinases in rewiring cellular metabolic homeostasis to drive tumor progression, thereby broadening the functional role of cell cycle regulators in human cancer. It is notable that BHB has shown an anti-tumor role in human colon cancer, encouraging the usage of ketogenic diets or ketone supplements as adjunct to conventional cancer therapies. In contrast, we reveal that BHB contributes to acute lymphoblastic leukemia, indicating that ketogenic nutrition strategy should be taken with caution by leukemia patients. Hence, the development of dietary interventions as cancer therapy should be grounded in the molecular pathogenesis of specific cancer cases. Our findings also suggest that blockade of the ketogenic pathway holds great promise in treatment of cancers with BHB dependency.