https://phaidra.vetmeduni.ac.at/o:4047 Cyclin C promotes development and progression of B-cell acute lymphoblastic leukemia by counteracting p53-mediated stress responses Trifinopoulos, Jana Jana Trifinopoulos 0000-0003-3163-5001 University of Veterinary Medicine Vienna List, Julia Julia List University of Veterinary Medicine Vienna Klampfl, Thorsten Thorsten Klampfl 0000-0002-6666-9773 University of Veterinary Medicine Vienna Klein, Klara Klara Klein University of Veterinary Medicine Vienna Prchal-Murphy, Michaela Michaela Prchal-Murphy University of Veterinary Medicine Vienna Witalisz-Siepracka, Agnieszka Agnieszka Witalisz-Siepracka 0000-0003-0237-0745 University of Veterinary Medicine Vienna Bellutti, Florian Florian Bellutti Fava, Luca L. Luca L. Fava Heller, Gerwin Gerwin Heller Stummer, Sarah Sarah Stummer Testori, Patricia Patricia Testori University of Veterinary Medicine Vienna Den Boer, Monique L. Monique L. Den Boer Boer, Judith M. Judith M. Boer Marinovic, Sonja Sonja Marinovic Hoermann, Gregor Gregor Hoermann Walter, Wencke Wencke Walter Villunger, Andreas Andreas Villunger Sicinski, Piotr Piotr Sicinski Sexl, Veronika Veronika Sexl 0000-0001-9363-0412 University of Veterinary Medicine Vienna Gotthardt, Dagmar Dagmar Gotthardt 0000-0002-8416-1236 University of Veterinary Medicine Vienna Ferrata Storti Foundation journal article open access eng Despite major therapeutic advances in the treatment of acute lymphoblastic leukemia (ALL), resistances and long-term toxicities still pose significant challenges. Cyclins and their associated cyclin-dependent kinases are one focus of cancer research when looking for targeted therapies. We discovered cyclin C to be a key factor for B-cell ALL (B-ALL) development and maintenance. While cyclin C is not essential for normal hematopoiesis, Ccnc?/? BCR::ABL1+ B-ALL cells fail to elicit leukemia in mice. RNA sequencing experiments revealed a p53 pathway deregulation in Ccnc?/? BCR::ABL1+ cells resulting in the inability of the leukemic cells to adequately respond to stress. A genome-wide CRISPR/Cas9 loss-of-function screen supplemented with additional knock-outs unveiled a dependency of human B-lymphoid cell lines on CCNC. High cyclin C levels in B-cell precursor (BCP) ALL patients were associated with poor event-free survival and increased risk of early disease recurrence after remission. Our findings highlight cyclin C as a potential therapeutic target for B-ALL, particularly to enhance cancer cell sensitivity to stress and chemotherapy. Tumor Suppressor Protein p53 Metabolism Tumor Suppressor Protein p53 Genetics Humans Animals Mice Cyclin C Metabolism Cyclin C Genetics Precursor B-Cell Lymphoblastic Leukemia-Lymphoma Metabolism Precursor B-Cell Lymphoblastic Leukemia-Lymphoma Pathology Precursor B-Cell Lymphoblastic Leukemia-Lymphoma Genetics Stress, Physiological Disease Progression Cell Line, Tumor http://creativecommons.org/licenses/by/4.0/ https://phaidra.vetmeduni.ac.at/api/object/o:4047/download 10.3324/haematol.2024.285701 https://phaidra.vetmeduni.ac.at/o:605 application/pdf Haematologica issn:1592-8721 VoR Haematologica 110 4 2.45 MB 2025