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
Affiliations
Jana Trifinopoulos
Department for Biological Sciences and Pathobiology, University of Veterinary Medicine, Vienna
Julia List
Department for Biological Sciences and Pathobiology, University of Veterinary Medicine, Vienna
Thorsten Klampfl
Department for Biological Sciences and Pathobiology, University of Veterinary Medicine, Vienna
Klara Klein
Department for Biological Sciences and Pathobiology, University of Veterinary Medicine, Vienna
Michaela Prchal-Murphy
Department for Biological Sciences and Pathobiology, University of Veterinary Medicine, Vienna
Agnieszka Witalisz-Siepracka
Department for Biological Sciences and Pathobiology, University of Veterinary Medicine, Vienna, Austria; Department of Pharmacology, Physiology and Microbiology, Division Pharmacology, Karl Landsteiner University of Health Sciences, Krems
Florian Bellutti
Armenise-Harvard Laboratory of Cell Division, Department of Cellular, Computational and Integrative Biology - CIBIO, University of Trento, Trento
Luca L. Fava
Armenise-Harvard Laboratory of Cell Division, Department of Cellular, Computational and Integrative Biology - CIBIO, University of Trento, Trento
Gerwin Heller
Division of Oncology, Department of Medicine I, Medical University of Vienna, Vienna
Sarah Stummer
Department for Biological Sciences and Pathobiology, University of Veterinary Medicine, Vienna
Patricia Testori
Department for Biological Sciences and Pathobiology, University of Veterinary Medicine, Vienna
Monique L. den Boer
Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Erasmus MC-Sophia Children’s Hospital, Rotterdam
Judith M. Boer
Princess Máxima Center for Pediatric Oncology, Utrecht
Sonja Marinovic
Division of Molecular Medicine, Laboratory of Personalized Medicine, Ruder Boskovic Institute, Zagreb, Croatia
Gregor Hoermann
MLL Munich Leukemia Laboratory, Munich
Wencke Walter
MLL Munich Leukemia Laboratory, Munich
Andreas Villunger
Institute for Developmental Immunology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria; Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (LBI-RUD), Vienna, Austria; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna
Piotr Sicinski
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA
Veronika Sexl
Department for Biological Sciences and Pathobiology, University of Veterinary Medicine, Vienna, Austria; University of Innsbruck, Innsbruck
Dagmar Gotthardt
Department for Biological Sciences and Pathobiology, University of Veterinary Medicine, Vienna
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.
