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Although comprehensive analysis of genetic abnormalities has led to the classification of lymphomas, the exact mechanism of lymphomagenesis remains elusive. The Ets family transcription factor, PU.1, encoded by <jats:italic>Spi1<\/jats:italic>, is essential for the development of myeloid and lymphoid cells. Our previous research illustrated the tumor suppressor function of PU.1 in classical Hodgkin lymphoma and myeloma cells. In the current study, we found that patients with DLBCL exhibited notably reduced PU.1 expression in their lymphoma cells, particularly in the non\u2010germinal center B\u2010cell\u2010like (GCB) subtype. This observation suggests that downregulation of PU.1 may be implicated in DLBCL tumor growth. To further assess PU.1's role in mature B cells in\u00a0vivo, we generated conditional <jats:italic>Spi1<\/jats:italic> knockout mice using <jats:italic>C\u03b31\u2010Cre<\/jats:italic> mice. Remarkably, 13 of the 23 knockout mice (56%) showed splenomegaly, lymphadenopathy, or masses, with some having histologically confirmed B\u2010cell lymphomas. In contrast, no wild\u2010type mice developed B\u2010cell lymphoma. In addition, RNA\u2010seq analysis of lymphoma cells from <jats:italic>C\u03b31\u2010Cre Spi1<\/jats:italic><jats:sup><jats:italic>F\/F<\/jats:italic><\/jats:sup> mice showed high frequency of each monoclonal CDR3 sequence, indicating that these lymphoma cells were monoclonal tumor cells. When these B lymphoma cells were transplanted into immunodeficient recipient mice, all mice died within 3\u2009weeks. Lentiviral\u2010transduced <jats:italic>Spi1<\/jats:italic> rescued 60% of the recipient mice, suggesting that PU.1 has a tumor suppressor function in\u00a0vivo. Collectively, PU.1 is a tumor suppressor in mature B cells, and decreased PU.1 results in mature B\u2010cell lymphoma development.<\/jats:p>","DOI":"10.1111\/cas.16344","type":"journal-article","created":{"date-parts":[[2024,9,25]],"date-time":"2024-09-25T21:47:01Z","timestamp":1727300821000},"page":"3890-3901","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Decreased PU.1 expression in mature B cells induces lymphomagenesis"],"prefix":"10.1111","volume":"115","author":[{"given":"Shinya","family":"Endo","sequence":"first","affiliation":[{"name":"Department of Hematology, Rheumatology, and Infectious Disease Kumamoto University Graduate School of Medicine  Kumamoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nao","family":"Nishimura","sequence":"additional","affiliation":[{"name":"Department of Hematology, Rheumatology, and Infectious Disease Kumamoto University Graduate School of Medicine 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