Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390.
Proc Natl Acad Sci U S A. 2024 Jul 30;121(31):e2409232121. doi: 10.1073/pnas.2409232121. Epub 2024 Jul 24.
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 , 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.
尽管有延长 B 细胞白血病和淋巴瘤生存期的治疗方法，但这些癌症中的许多仍然无法治愈。因此，需要开发新的分子靶点和治疗方法来扩大治疗选择。为了确定新的分子靶点，我们使用小鼠正向遗传筛选来鉴定发育或淋巴细胞存活所需的基因。在这里，我们描述了一个必需基因，该基因编码一种锌指蛋白，对于正常和恶性淋巴细胞的存活是必需的。我们表明，ZFP574 与锌指蛋白 THAP12 相互作用，并在细胞周期进程中促进 G1 期到 S 期的转变。ZFP574 的突变会损害 ZFP574-THAP12 复合物的核定位。ZFP574 或 THAP12 的缺失会导致细胞周期停滞和淋巴增殖受损。ZFP574 的种系突变、急性基因缺失或靶向降解抑制了小鼠中 Myc 驱动的 B 细胞白血病，但正常 B 细胞基本不受影响，允许长期存活，而对照动物则观察到完全致死。我们的研究结果支持了靶向 ZFP574-THAP12 的药物作为治疗 B 细胞恶性肿瘤的独特策略的鉴定。
