Jana Trifinopoulos Jana Trifinopoulos Julia List Julia List Thorsten Klampfl Thorsten Klampfl Klara Klein Klara Klein Michaela Prchal-Murphy Michaela Prchal-Murphy Agnieszka Witalisz-Siepracka Agnieszka Witalisz-Siepracka Florian Bellutti Florian Bellutti Luca L. Fava Luca L. Fava Gerwin Heller Gerwin Heller Sarah Stummer Sarah Stummer Patricia Testori Patricia Testori Monique L. Den Boer Monique L. Den Boer Judith M. Boer Judith M. Boer Sonja Marinovic Sonja Marinovic Gregor Hoermann Gregor Hoermann Wencke Walter Wencke Walter Andreas Villunger Andreas Villunger Piotr Sicinski Piotr Sicinski Veronika Sexl Veronika Sexl Dagmar Gotthardt Dagmar Gotthardt Ferrata Storti Foundation 2025 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. PDFDocument eng 2025-04-14T08:26:51.847255Z 2025 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 2573857 b application/pdf http://creativecommons.org/licenses/by/4.0/