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In rare cases, expression of a single transcription factor, or a few key factors, may be sufficient to dictate lineage differentiation in a precursor cell. The E26\u2010transformation\u2010specific\u2010family transcription factor Spi\u2010C has emerged as an example of a lineage\u2010instructive factor involved in the generation of mature, specialized subsets of both myeloid and lymphoid cells. Spi\u2010C can instruct differentiation of splenic precursors into red pulp macrophages responsible for phagocytosing senescent red blood cells. In the B cell compartment, Spi\u2010C acts as a key regulator of cell fate decisions at the pro\u2010B to pre\u2010B cell stage and for plasma cell differentiation. Spi\u2010C regulates key genes including <jats:italic>Nfkb1<\/jats:italic>, <jats:italic>Bach2<\/jats:italic>, <jats:italic>Syk<\/jats:italic>, and <jats:italic>Blnk<\/jats:italic> to regulate cell cycle entry and B cell differentiation. Here, we review the biology of the lineage\u2010instructive transcription factor Spi\u2010C and its contribution to mechanisms of disease in macrophages and B cells.<\/jats:p><jats:p>This article is categorized under:<jats:list list-type=\"simple\">\n<jats:list-item><jats:p>Cancer &gt; Molecular and Cellular Physiology<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Immune System Diseases &gt; Molecular and Cellular Physiology<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Infectious Diseases &gt; Genetics\/Genomics\/Epigenetics<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p>","DOI":"10.1002\/wsbm.1519","type":"journal-article","created":{"date-parts":[[2021,3,1]],"date-time":"2021-03-01T15:34:13Z","timestamp":1614612853000},"source":"Crossref","is-referenced-by-count":5,"title":["Lineage\u2010instructive functions of the <scp>E26<\/scp>\u2010transformation\u2010specific\u2010family transcription factor <scp>Spi\u2010C<\/scp> in immune cell development and disease"],"prefix":"10.1002","volume":"13","author":[{"given":"Hannah L.","family":"Raczkowski","sequence":"first","affiliation":[{"name":"Department of Microbiology &amp; Immunology and the Center for Human Immunology, Schulich School of Medicine and Dentistry Western University  London Ontario Canada"},{"name":"Division of Genetics and Development, Children's Health Research Institute Lawson Research Institute  London Ontario 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 &amp; Immunology and the Center for Human Immunology, Schulich School of Medicine and Dentistry Western University  London Ontario Canada"},{"name":"Division of Genetics and Development, Children's Health Research Institute Lawson Research Institute  London Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2021,3]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aao5213"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.00033"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2020.107825"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI92504"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2007.07.004"},{"volume-title":"Encyclopedia of signaling molecules","year":"2018","author":"Batista C. 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