https://phaidra.vetmeduni.ac.at/o:3977 CDK6 kinase inhibition unmasks metabolic dependencies in BCR::ABL1+ leukemia Scheiblecker, Lisa Lisa Scheiblecker University of Veterinary Medicine Vienna Klampfl, Thorsten Thorsten Klampfl 0000-0002-6666-9773 University of Veterinary Medicine Vienna Doma, Eszter Eszter Doma University of Veterinary Medicine Vienna Nebenfuehr, Sofie Sofie Nebenfuehr University of Veterinary Medicine Vienna Torres-Quesada, Omar Omar Torres-Quesada Strich, Sophie Sophie Strich Heller, Gerwin Gerwin Heller 0000-0001-8742-5631 Werdenich, Daniela Daniela Werdenich University of Veterinary Medicine Vienna Tschulenk, Waltraud Waltraud Tschulenk University of Veterinary Medicine Vienna Zojer, Markus Markus Zojer University of Veterinary Medicine Vienna Bellutti, Florian Florian Bellutti University of Veterinary Medicine Vienna Schirripa, Alessia Alessia Schirripa 0000-0001-5446-9136 University of Veterinary Medicine Vienna Zöchbauer-Müller, Sabine Sabine Zöchbauer-Müller Valent, Peter Peter Valent Walter, Ingrid Ingrid Walter 0000-0002-5038-188X University of Veterinary Medicine Vienna Stefan, Eduard Eduard Stefan Sexl, Veronika Veronika Sexl 0000-0001-9363-0412 University of Veterinary Medicine Vienna Kollmann, Karoline Karoline Kollmann 0000-0002-7937-4245 University of Veterinary Medicine Vienna Springer Nature journal article open access eng 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. 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 http://creativecommons.org/licenses/by/4.0/ https://phaidra.vetmeduni.ac.at/api/object/o:3977/download 10.1038/s41419-025-07434-1 https://phaidra.vetmeduni.ac.at/o:605 application/pdf Cell Death & Diseases issn:2041-4889 VoR Cell Death & Diseases 16 1 3.35 MB 2024