Despite the availability of life-extending treatments for B cell leukemias and lymphomas, many of these cancers remain incurable. Thus, the development of new molecular targets and therapeutics is needed to expand treatment options. To identify new molecular targets, we used a forward genetic screen in mice to identify genes required for development or survival of lymphocytes. Here, we describe Zfp574 , an essential gene encoding a zinc finger protein necessary for normal and malignant lymphocyte survival. We show that ZFP574 interacts with zinc finger protein THAP12 and promotes the G1-to-S-phase transition during cell cycle progression. Mutation of ZFP574 impairs nuclear localization of the ZFP574–THAP12 complex. ZFP574 or THAP12 deficiency results in cell cycle arrest and impaired lymphoproliferation. Germline mutation, acute gene deletion, or targeted degradation of ZFP574 suppressed Myc-driven B cell leukemia in mice, but normal B cells were largely spared, permitting long-term survival, whereas complete lethality was observed in control animals. Our findings support the identification of drugs targeting ZFP574–THAP12 as a unique strategy to treat B cell malignancies.

中文翻译：

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ZFP574-THAP12 复合物的破坏可抑制小鼠 B 细胞恶性肿瘤


尽管有针对 B 细胞白血病和淋巴瘤的延长生命的治疗方法，但其中许多癌症仍然无法治愈。因此，需要开发新的分子靶点和治疗方法来扩大治疗选择。为了识别新的分子靶标，我们在小鼠中使用了正向遗传筛选来识别淋巴细胞发育或存活所需的基因。在这里，我们描述Zfp574 ，编码正常和恶性淋巴细胞存活所必需的锌指蛋白的必需基因。我们发现 ZFP574 与锌指蛋白 THAP12 相互作用，并促进细胞周期进程中 G1 至 S 相的转变。 ZFP574 的突变会损害 ZFP574-THAP12 复合物的核定位。 ZFP574 或 THAP12 缺陷会导致细胞周期停滞和淋巴细胞增殖受损。种系突变、急性基因缺失或 ZFP574 的靶向降解抑制了小鼠中 Myc 驱动的 B 细胞白血病，但正常 B 细胞很大程度上幸免于难，允许长期存活，而在对照动物中观察到完全致死。我们的研究结果支持确定靶向 ZFP574-THAP12 的药物作为治疗 B 细胞恶性肿瘤的独特策略。