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

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

Research output: Journal article (peer-reviewed)Journal article

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 as a key factor for B-ALL development and maintenance. While cyclin C is non-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 incapability 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 potential therapeutic target for B-ALL, particularly to enhance cancer cell sensitivity to stress and chemotherapy.

Original languageEnglish
JournalHaematologica
DOIs
Publication statusE-pub ahead of print - 10 Oct 2024

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