Cyclin C promotes development and progression of B-cell acute lymphoblastic leukemia by counteracting p53-mediated stress responses

Trifinopoulos, Jana; List, Julia; Klampfl, Thorsten; Klein, Klara; Prchal-Murphy, Michaela; Witalisz-Siepracka, Agnieszka; Bellutti, Florian; Fava, Luca L.; Heller, Gerwin; Stummer, Sarah; Testori, Patricia; Den Boer, Monique L.; Boer, Judith M.; Marinović, Sonja; Hoermann, Gregor; Walter, Wencke; Villunger, Andreas; Sicinski, Piotr; Sexl, Veronika; Gotthardt, Dagmar (2024) Cyclin C promotes development and progression of B-cell acute lymphoblastic leukemia by counteracting p53-mediated stress responses. Haematologica, 110 (4). pp. 877-892. ISSN 0390-6078

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Abstract

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, CcncΔ/Δ BCR::ABL1+ B-ALL cells fail to elicit leukemia in mice. RNA sequencing experiments revealed a p53 pathway deregulation in CcncΔ/Δ 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.

Item Type:	Article
Uncontrolled Keywords:	cyclin C; B-cell acute lymphoblastic leukemia; p53
Subjects:	BIOMEDICINE AND HEALTHCARE BIOMEDICINE AND HEALTHCARE > Basic Medical Sciences BIOMEDICINE AND HEALTHCARE > Basic Medical Sciences > Immunology
Divisions:	Division of Molecular Medicine
Depositing User:	Sonja Marinović
Date Deposited:	11 Dec 2025 12:28
URI:	http://fulir.irb.hr/id/eprint/10411
DOI:	10.3324/haematol.2024.285701

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