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, 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.
Authors
- Andreas Villunger (ORCID: https://orcid.org/0000-0001-8259-4153)
- Judith M. Boer (ORCID: https://orcid.org/0000-0003-4848-7789)
- Julia List (ORCID: https://orcid.org/0000-0002-4199-3198)
- Gregor Hoermann (ORCID: https://orcid.org/0000-0002-7374-4380)
- Monique L. den Boer (ORCID: https://orcid.org/0000-0002-5795-2921)
- Gerwin Heller (ORCID: https://orcid.org/0000-0001-8742-5631)
- Sonja Marinović (ORCID: https://orcid.org/0000-0002-4054-338X)
- Agnieszka Witalisz‐Siepracka (ORCID: https://orcid.org/0000-0003-0237-0745)
- Thorsten Klampfl (ORCID: https://orcid.org/0000-0002-6666-9773)
- Wencke Walter (ORCID: https://orcid.org/0000-0002-5083-9838)
- Luca L. Fava (ORCID: https://orcid.org/0000-0002-6741-1723)
- Michaela Prchal‐Murphy
- Jana Trifinopoulos (ORCID: https://orcid.org/0000-0003-3163-5001)
- Piotr Siciński (ORCID: https://orcid.org/0000-0002-8859-5234)
- Veronika Sexl (ORCID: https://orcid.org/0000-0001-9363-0412)
- Klara R. Klein (ORCID: https://orcid.org/0000-0002-5894-9054)
- Florian Bellutti (ORCID: https://orcid.org/0000-0003-2095-4971)
- Dagmar Gotthardt (ORCID: https://orcid.org/0000-0002-8416-1236)
- Sarah Stummer
- Patricia Testori
Institutions
- Harvard University (US)
- Austrian Academy of Sciences (AT)
- Innsbruck Medical University (AT)
- University of Veterinary Medicine Vienna (AT)
- Universität Innsbruck (AT)
- University of Trento (IT)
- Munich Leukemia Laboratory (Germany) (DE)
- Boston VA Research Institute (US)
- Dana-Farber Cancer Institute (US)
- Ruđer Bošković Institute (HR)
- Princess Máxima Center (NL)
- CeMM Research Center for Molecular Medicine (AT)
- Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (AT)
- Erasmus MC - Sophia Children’s Hospital (NL)
- Karl Landsteiner University of Health Sciences (AT)
- Medical University of Vienna (AT)
Publication Details
- Journal
- Haematologica
- Published
- 2024-10-10
- DOI
- https://doi.org/10.3324/haematol.2024.285701
- Citations
- 2
- Primary Topic
- Acute Lymphoblastic Leukemia research
- Type
- article
- Field-Weighted Citation Impact
- 1.09
Funders
- Austrian Science Fund