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

Publikationen als Autor:in / Herausgeber:in der Vetmeduni

Trifinopoulos, Jana; Klampfl, Thorsten; List, Julia; Gotthardt-Pötsch, Dagmar; Prchal-Murphy, Michaela; Sexl, Veronika; Testori, Patricia

Abstrakt

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

Dokumententyp

Originalarbeit

Open Access Type

Gold

DOI

10.3324/haematol.2024.285701

PubMed ID

MEDLINE:39385738

Projekt

Molecular and Cellular Control of Tissue Homeostasis in Health and Disease