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Disruption of the ZFP574-THAP12 complex suppresses B cell malignancies in mice.

Authors :
Xue Zhong
Moresco, James J.
SoRelle, Jeffrey A.
Ran Song
Yiao Jiang
Nguyen, Mylinh T.
Jianhui Wang
Chun Hui Bu
Moresco, Eva Marie Y.
Beutler, Bruce
Jin Huk Choi
Source :
Proceedings of the National Academy of Sciences of the United States of America; 7/30/2024, Vol. 121 Issue 31, p1-8, 22p
Publication Year :
2024

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. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
00278424
Volume :
121
Issue :
31
Database :
Complementary Index
Journal :
Proceedings of the National Academy of Sciences of the United States of America
Publication Type :
Academic Journal
Accession number :
178895975
Full Text :
https://doi.org/10.1073/pnas.2409232121