Lisa Scheiblecker Lisa Scheiblecker Thorsten Klampfl Thorsten Klampfl Eszter Doma Eszter Doma Sofie Nebenfuehr Sofie Nebenfuehr Omar Torres-Quesada Omar Torres-Quesada Sophie Strich Sophie Strich Gerwin Heller Gerwin Heller Daniela Werdenich Daniela Werdenich Waltraud Tschulenk Waltraud Tschulenk Markus Zojer Markus Zojer Florian Bellutti Florian Bellutti Alessia Schirripa Alessia Schirripa Sabine Zöchbauer-Müller Sabine Zöchbauer-Müller Peter Valent Peter Valent Ingrid Walter Ingrid Walter Eduard Stefan Eduard Stefan Veronika Sexl Veronika Sexl Karoline Kollmann Karoline Kollmann Springer Nature 2024 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. PDFDocument eng 2025-03-26T10:01:46.098174Z 2024 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 3508455 b application/pdf http://creativecommons.org/licenses/by/4.0/