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IKZF3 mutations are associated with human diseases including immunodeficiency, leukemia, and lymphoma. H195Y IKZF3 mutation was discovered in a mouse model of precursor B cell acute lymphoblastic leukemia. Forced expression of H195Y IKZF3 in precursor B (pre-B) cells altered gene expression changes induced by IL-7. The goal of this study was to determine how H195Y mutation of IKZF3 affects its regulation of target genes. To address this goal, we determined the effect of wild-type (WT) versus mouse H195Y or human H196Y IKZF3 on 3 direct target genes: Cish, Il7r, and Igll1. We found that mouse or human IKZF3 repressed Cish, Il7r, and Igll1 promoter reporter activity in transiently transfected pre-B acute lymphoblastic leukemia cell lines. H195Y IKZF3 failed to repress Cish, Il7r, and Igll1 promoter activity. Stable transduction with mouse H195Y or human H196Y IKZF3 increased endogenous Cish and Igll1 gene expression in pre-B acute lymphoblastic leukemia cell lines. H196Y IKZF3 had increased stability compared with WT IKZF3 in transduced cells, with a half-life of 10.3\u2005h compared with 6.0\u2005h for WT IKZF3. In summary, first, these experiments suggest that H195Y\/H196Y mutation of IKZF3 impairs transcriptional repression activity of IKZF3. Second, this mutation increases protein stability, resulting in higher levels of protein expression. This study provides insight into mechanisms by which IKZF3 mutations promote immunodeficiency, leukemia, and lymphoma.<\/jats:p>","DOI":"10.1093\/jleuko\/qiag001","type":"journal-article","created":{"date-parts":[[2026,1,2]],"date-time":"2026-01-02T12:33:43Z","timestamp":1767357223000},"source":"Crossref","is-referenced-by-count":0,"title":["H195Y mutation of IKZF3 identified in a mouse model of precursor B cell acute lymphoblastic leukemia impairs transcriptional repression activity and increases protein stability"],"prefix":"10.1093","volume":"118","author":[{"given":"Heidi","family":"Rysan","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, Western University , 1151 Richmond Street, London, Ontario N6A 5C1 ,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James A","family":"Iansavitchous","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, Western University , 1151 Richmond Street, London, Ontario N6A 5C1 ,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Trevor M","family":"Day","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, Western University , 1151 Richmond Street, London, Ontario N6A 5C1 ,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Uribe","family":"Estrada","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, Western University , 1151 Richmond Street, London, Ontario N6A 5C1 ,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Esther","family":"Dou","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, Western University , 1151 Richmond Street, London, Ontario N6A 5C1 ,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sheena","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, Western University , 1151 Richmond Street, London, Ontario N6A 5C1 ,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leon H","family":"Baronijan","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, Western University , 1151 Richmond Street, London, Ontario N6A 5C1 ,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9201-1983","authenticated-orcid":false,"given":"Rodney P","family":"DeKoter","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Schulich School of 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