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.

中文翻译：

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Cyclin C 通过抵消 p53 介导的应激反应促进 B 细胞急性淋巴细胞白血病的发生和进展。


尽管急性淋巴细胞白血病 （ALL） 的治疗取得了重大进展，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重点之一。我们发现细胞周期蛋白 C 是 B-ALL 开发和维护的关键因子。虽然细胞周期蛋白 C 对于正常造血不是必需的，但 CcncΔ/Δ BCR：：ABL1+ B-ALL 细胞无法在小鼠中引发白血病。RNA 测序实验显示 CcncΔ/Δ BCR：：ABL1+ 细胞中的 p53 通路失调，导致白血病细胞无法充分响应应激。补充额外敲除的全基因组 CRISPR/Cas9 功能丧失筛选揭示了人 B 淋巴细胞系对 CCNC 的依赖性。B 细胞前体 （BCP） ALL 患者的高细胞周期蛋白 C 水平与无事件生存率差和缓解后早期疾病复发风险增加相关。我们的研究结果强调细胞周期蛋白 C 是 B-ALL 的潜在治疗靶点，特别是增强癌细胞对压力和化疗的敏感性。