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Chromosomal rearrangements in PAX5 account for 2\u20133% of B\u2010ALL cases, and most lead to the expression of in\u2010frame fusion transcripts. These fusions can encode chimeric proteins composed of the N\u2010terminal portion of PAX5 and the C\u2010terminal region of a variety of heterogeneous fusion partners. We analyzed the function of PAX5::CBFA2T3 (PAX5\u2010C), a fusion protein found in B\u2010cell acute lymphoblastic leukemia. PAX5\u2010C strongly repressed PAX5 transcriptional activity in luciferase assays. In co\u2010immunoprecipitation assays, PAX5\u2010C bound to PAX5 and HDAC1\/3. However, neither HDAC knockdown nor treatment with a HDAC inhibitor showed any effect on the repression of PAX5 transactivity by PAX5\u2010C. In addition, PAX5\u2010C with DNA binding\u2010defective mutations (PAX5 M\u2010C) could still repress PAX5 transactivity; however, the repression of PAX5 transactivity by PAX5 M\u2010C was abolished by inhibition or knockdown of HDAC. These findings indicate that PAX5\u2010C exhibits two mechanisms of repression: a DNA binding\u2010dependent and a HDAC\u2010dependent mechanism, with either being sufficient for the repression of PAX5 transactivity by PAX5\u2010C. We performed ChIP\u2010qPCR under conditions of the luciferase assay and inferred that these two mechanisms involved the inhibition of direct binding of PAX5 to the promoter due to promoter occupancy by PAX5\u2010C, and recruitment of HDAC1\/3 to the PAX5 transcription complex by the binding of PAX5\u2010C to PAX5 on the promoter. The present results provide novel insight into the mechanisms of how PAX5\u2010fusion proteins inhibit PAX5 function.<\/jats:p>","DOI":"10.1002\/2211-5463.70087","type":"journal-article","created":{"date-parts":[[2025,7,11]],"date-time":"2025-07-11T11:28:37Z","timestamp":1752233317000},"page":"1789-1799","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Two\u2010way inhibition of\n                    <scp>PAX5<\/scp>\n                    transcriptional activity by\n                    <scp>PAX5<\/scp>\n                    ::\n                    <scp>CBFA2T3<\/scp>"],"prefix":"10.1002","volume":"15","author":[{"given":"Reina","family":"Ueno","sequence":"first","affiliation":[{"name":"Division of Cellular and Genetic Sciences, Department of Integrated Health Sciences Nagoya University Graduate School of Medicine  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