phaidra.vetmeduni.ac.at o:3977 DOI 10.1038/s41419-025-07434-1 CDK6 kinase inhibition unmasks metabolic dependencies in BCR::ABL1+ leukemia Metabolic reprogramming and cell cycle deregulation are hallmarks of cancer cells. The cell cycle kinase CDK6 has recently been implicated in a wide range of hematopoietic malignancies. We here investigate the role of CDK6 in the regulation of cellular metabolism in BCR::ABL1+ leukemic cells. Our study, using gene expression data and ChIP-Seq analysis, highlights the contribution of CDK6 kinase activity in the regulation of oxidative phosphorylation. Our findings imply a competition for promoter interaction of CDK6 with the master regulator of mitochondrial respiration, NRF-1. In line, cells lacking kinase active CDK6 display altered mitochondria morphology with a defective electron transport chain. The enhanced cytoplasm/mitochondria ATP ratio paralleled by high pyruvate and lactate levels indicate a metabolic switch to glycolysis. Accordingly, combinatorial treatment of leukemic cells including imatinib resistant cells with the CDK4/6 inhibitor palbociclib and the glycolysis inhibitor 2-deoxyglucose (2-DG) enhanced apoptosis, while blocking cell proliferation in leukemic cells. These data may open a new therapeutic avenue for hematologic malignancies with high CDK6 expression by exploiting metabolic vulnerabilities unmasked by blocking CDK6 kinase activity that might even be able to overcome imatinib resistance. eng Humans Cyclin-Dependent Kinase 6 Metabolism Cyclin-Dependent Kinase 6 Antagonists & Inhibitors Fusion Proteins, bcr-abl Genetics Fusion Proteins, bcr-abl Metabolism Glycolysisdrug Effects Protein Kinase Inhibitors Pharmacology Piperazines Pharmacology Cell Line, Tumor Mitochondria Metabolism Mitochondria Drug Effects Apoptosisdrug Effects Oxidative Phosphorylation Drug Effects Cell Proliferation Cell Drug Effects Deoxy Glucose Deoxy Pharmacology Pyridines Pharmacology Leukemia, Myelogenous, Chronic, BCR-ABL Positive Metabolism Leukemia, Myelogenous, Chronic, BCR-ABL Positive Drug Therapy Leukemia, Myelogenous, Chronic, BCR-ABL Positive Pathology Leukemia, Myelogenous, Chronic, BCR-ABL Positive Genetics Imatinib Mesylate Pharmacology Imatinib Mesylate Therapeutic Use Drug Resistance, Neoplasm Drug Effects K562 Cells 2025-03-26T10:01:46.899Z LOMv1.0 Author BEGIN:VCARD VERSION:3.0 N:Scheiblecker;Lisa; FN:Lisa Scheiblecker END:VCARD BEGIN:VCARD VERSION:3.0 N:Klampfl;Thorsten; FN:Thorsten Klampfl X-ORCID:https://orcid.org/0000-0002-6666-9773 END:VCARD BEGIN:VCARD VERSION:3.0 N:Doma;Eszter; FN:Eszter Doma END:VCARD BEGIN:VCARD VERSION:3.0 N:Nebenfuehr;Sofie; FN:Sofie Nebenfuehr END:VCARD BEGIN:VCARD VERSION:3.0 N:Torres-Quesada;Omar; FN:Omar Torres-Quesada END:VCARD BEGIN:VCARD VERSION:3.0 N:Strich;Sophie; FN:Sophie Strich END:VCARD BEGIN:VCARD VERSION:3.0 N:Heller;Gerwin; FN:Gerwin Heller X-ORCID:https://orcid.org/0000-0001-8742-5631 END:VCARD BEGIN:VCARD VERSION:3.0 N:Werdenich;Daniela; FN:Daniela Werdenich END:VCARD BEGIN:VCARD VERSION:3.0 N:Tschulenk;Waltraud; FN:Waltraud Tschulenk END:VCARD BEGIN:VCARD VERSION:3.0 N:Zojer;Markus; FN:Markus Zojer END:VCARD BEGIN:VCARD VERSION:3.0 N:Bellutti;Florian; FN:Florian Bellutti END:VCARD BEGIN:VCARD VERSION:3.0 N:Schirripa;Alessia; FN:Alessia Schirripa X-ORCID:https://orcid.org/0000-0001-5446-9136 END:VCARD BEGIN:VCARD VERSION:3.0 N:Zöchbauer-Müller;Sabine; FN:Sabine Zöchbauer-Müller END:VCARD BEGIN:VCARD VERSION:3.0 N:Valent;Peter; FN:Peter Valent END:VCARD BEGIN:VCARD VERSION:3.0 N:Walter;Ingrid; FN:Ingrid Walter X-ORCID:https://orcid.org/0000-0002-5038-188X END:VCARD BEGIN:VCARD VERSION:3.0 N:Stefan;Eduard; FN:Eduard Stefan END:VCARD BEGIN:VCARD VERSION:3.0 N:Sexl;Veronika; FN:Veronika Sexl X-ORCID:https://orcid.org/0000-0001-9363-0412 END:VCARD BEGIN:VCARD VERSION:3.0 N:Kollmann;Karoline; FN:Karoline Kollmann X-ORCID:https://orcid.org/0000-0002-7937-4245 END:VCARD https://w3id.org/kim/hcrt/scheme https://w3id.org/kim/hcrt/text Textdokument Text LOMv1.0 yes https://creativecommons.org/licenses/by/4.0 application/pdf 3508455 https://phaidra.vetmeduni.ac.at/o:3977 https://phaidra.vetmeduni.ac.at/api/object/o:3977/thumbnail LOMv1.0 discipline