University of Veterinary Medicine Vienna 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. en TEXT journal article Wissenschaftlicher Artikel Articolo di rivista Text Wissenschaftlicher Artikel Testo Articolo di rivista Text journal article 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 2024 2024 Lisa Scheiblecker Thorsten Klampfl Eszter Doma Sofie Nebenfuehr Omar Torres-Quesada Sophie Strich Gerwin Heller Daniela Werdenich Waltraud Tschulenk Markus Zojer Florian Bellutti Alessia Schirripa Sabine Zöchbauer-Müller Peter Valent Ingrid Walter Eduard Stefan Veronika Sexl Karoline Kollmann Springer Nature