phaidra.vetmeduni.ac.at o:4047 DOI 10.3324/haematol.2024.285701 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. eng 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 2025-04-14T08:26:52.683Z LOMv1.0 Author BEGIN:VCARD VERSION:3.0 N:Trifinopoulos;Jana; FN:Jana Trifinopoulos X-ORCID:https://orcid.org/0000-0003-3163-5001 END:VCARD BEGIN:VCARD VERSION:3.0 N:List;Julia; FN:Julia List END:VCARD BEGIN:VCARD VERSION:3.0 N:Klampfl;Thorsten; FN:Thorsten Klampfl X-ORCID:https://orcid.org/0000-0002-6666-9773 END:VCARD BEGIN:VCARD VERSION:3.0 N:Klein;Klara; FN:Klara Klein END:VCARD BEGIN:VCARD VERSION:3.0 N:Prchal-Murphy;Michaela; FN:Michaela Prchal-Murphy END:VCARD BEGIN:VCARD VERSION:3.0 N:Witalisz-Siepracka;Agnieszka; FN:Agnieszka Witalisz-Siepracka X-ORCID:https://orcid.org/0000-0003-0237-0745 END:VCARD BEGIN:VCARD VERSION:3.0 N:Bellutti;Florian; FN:Florian Bellutti END:VCARD BEGIN:VCARD VERSION:3.0 N:Fava;Luca L.; FN:Luca L. Fava END:VCARD BEGIN:VCARD VERSION:3.0 N:Heller;Gerwin; FN:Gerwin Heller END:VCARD BEGIN:VCARD VERSION:3.0 N:Stummer;Sarah; FN:Sarah Stummer END:VCARD BEGIN:VCARD VERSION:3.0 N:Testori;Patricia; FN:Patricia Testori END:VCARD BEGIN:VCARD VERSION:3.0 N:Den Boer;Monique L.; FN:Monique L. Den Boer END:VCARD BEGIN:VCARD VERSION:3.0 N:Boer;Judith M.; FN:Judith M. Boer END:VCARD BEGIN:VCARD VERSION:3.0 N:Marinovic;Sonja; FN:Sonja Marinovic END:VCARD BEGIN:VCARD VERSION:3.0 N:Hoermann;Gregor; FN:Gregor Hoermann END:VCARD BEGIN:VCARD VERSION:3.0 N:Walter;Wencke; FN:Wencke Walter END:VCARD BEGIN:VCARD VERSION:3.0 N:Villunger;Andreas; FN:Andreas Villunger END:VCARD BEGIN:VCARD VERSION:3.0 N:Sicinski;Piotr; FN:Piotr Sicinski END:VCARD BEGIN:VCARD VERSION:3.0 N:Sexl;Veronika; FN:Veronika Sexl X-ORCID:https://orcid.org/0000-0001-9363-0412 END:VCARD BEGIN:VCARD VERSION:3.0 N:Gotthardt;Dagmar; FN:Dagmar Gotthardt X-ORCID:https://orcid.org/0000-0002-8416-1236 END:VCARD https://w3id.org/kim/hcrt/scheme https://w3id.org/kim/hcrt/text Textdokument Text LOMv1.0 yes https://creativecommons.org/licenses/by/4.0 application/pdf 2573857 https://phaidra.vetmeduni.ac.at/o:4047 https://phaidra.vetmeduni.ac.at/api/object/o:4047/thumbnail LOMv1.0 discipline