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, Marinovic Sonja, Hoermann Gregor, Walter Wencke, Villunger Andreas, Sicinski Piotr, Sexl Veronika, Gotthardt Dagmar
Department for Biological Sciences and Pathobiology, University of Veterinary Medicine, Vienna.
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.
Haematologica. 2025 Apr 1;110(4):877-892. doi: 10.3324/haematol.2024.285701. Epub 2024 Oct 10.
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.
尽管在急性淋巴细胞白血病（ALL）的治疗方面取得了重大的治疗进展，但耐药性和长期毒性仍然构成重大挑战。在寻找靶向治疗方法时，细胞周期蛋白及其相关的细胞周期蛋白依赖性激酶是癌症研究的一个重点。我们发现细胞周期蛋白C是B细胞ALL（B-ALL）发生和维持的关键因素。虽然细胞周期蛋白C对正常造血不是必需的，但CcncΔ/Δ BCR::ABL1+ B-ALL细胞在小鼠中无法引发白血病。RNA测序实验揭示了CcncΔ/Δ BCR::ABL1+细胞中p53信号通路失调，导致白血病细胞无法充分应对应激。全基因组CRISPR/Cas9功能丧失筛选以及额外的基因敲除揭示了人类B淋巴细胞系对CCNC的依赖性。B细胞前体（BCP）ALL患者中细胞周期蛋白C水平高与无事件生存期差以及缓解后疾病早期复发风险增加相关。我们的研究结果突出了细胞周期蛋白C作为B-ALL潜在治疗靶点的作用，特别是增强癌细胞对应激和化疗的敏感性。
