University of Veterinary Medicine Vienna Cyclin C promotes development and progression of B-cell acute lymphoblastic leukemia by counteracting p53-mediated stress responses 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. en TEXT journal article Wissenschaftlicher Artikel Articolo di rivista Text journal article Testo Articolo di rivista Text Wissenschaftlicher Artikel 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 2025 2025 Jana Trifinopoulos Julia List Thorsten Klampfl Klara Klein Michaela Prchal-Murphy Agnieszka Witalisz-Siepracka Florian Bellutti Luca L. Fava Gerwin Heller Sarah Stummer Patricia Testori Monique L. Den Boer Judith M. Boer Sonja Marinovic Gregor Hoermann Wencke Walter Andreas Villunger Piotr Sicinski Veronika Sexl Dagmar Gotthardt Ferrata Storti Foundation