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Updated: Jun 19, 2025
Rapid Analysis of Chromosome Aberrations in Mouse B Lymphocytes by PNA-FISH
Published on: August 19, 2014
Disruption of the ZFP574-THAP12 complex suppresses B cell malignancies in mice
Xue Zhong1, James J Moresco1, Jeffrey A SoRelle2
1Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390.
Abstract:
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.
Insights
Researchers identified ZFP574, a gene crucial for lymphocyte survival. Targeting the ZFP574-THAP12 complex offers a novel therapeutic strategy for B cell malignancies like leukemia and lymphoma.
Area of Science:
- Hematology
- Molecular Biology
- Cancer Research
Background:
- B cell leukemias and lymphomas remain challenging to cure despite existing treatments.
- Novel molecular targets and therapeutics are essential for improving patient outcomes.
Purpose of the Study:
- To identify novel genes essential for lymphocyte survival and potential therapeutic targets in B cell malignancies.
- To characterize the role of the zinc finger protein ZFP574 in lymphocyte development and cancer.
Main Methods:
- A forward genetic screen in mice was employed to identify genes critical for lymphocyte survival.
- ZFP574's interaction with THAP12 and its role in cell cycle progression were investigated.
- The impact of ZFP574 deficiency on Myc-driven B cell leukemia was assessed in vivo.
Main Results:
- ZFP574 is essential for both normal and malignant lymphocyte survival, interacting with THAP12 to promote cell cycle progression.
- ZFP574 or THAP12 deficiency leads to cell cycle arrest and impaired lymphoproliferation.
- Targeting ZFP574 suppressed Myc-driven B cell leukemia in mice with minimal impact on normal B cells.
Conclusions:
- The ZFP574-THAP12 complex is a critical regulator of lymphocyte survival and proliferation.
- Targeting the ZFP574-THAP12 interaction presents a promising and specific therapeutic strategy for B cell malignancies.
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