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We show that c-MYC facilitates B-cell proliferation as a protumorigenic driver and unexpectedly coengages counteracting tumor suppression through its downstream factor TFAP4. TFAP4 is mutated in human lymphoid malignancies, particularly in &amp;gt;10% of Burkitt lymphomas, and reduced TFAP4 expression was associated with poor survival of patients with MYC-high B-cell acute lymphoblastic leukemia. In mice, insufficient TFAP4 expression accelerated c-MYC\u2013driven transformation of B cells. Mechanistically, c-MYC suppresses the stemness of developing B cells by inducing TFAP4 and restricting self-renewal of proliferating B cells. Thus, the pursuant transcription factor cascade functions as a tumor suppressor module that safeguards against the transformation of developing B cells.<\/jats:p>","DOI":"10.1182\/blood.2021011711","type":"journal-article","created":{"date-parts":[[2021,7,20]],"date-time":"2021-07-20T18:04:24Z","timestamp":1626804264000},"page":"2526-2538","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":10,"title":["Unexpected suppression of tumorigenesis by c-MYC via TFAP4-dependent restriction of stemness in B lymphocytes"],"prefix":"10.1182","volume":"138","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6604-6496","authenticated-orcid":false,"given":"Elena","family":"Tonc","sequence":"first","affiliation":[{"name":"Department of Pathology and Immunology and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2637-7696","authenticated-orcid":false,"given":"Yoshiko","family":"Takeuchi","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7147-4236","authenticated-orcid":false,"given":"Chun","family":"Chou","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6397-1205","authenticated-orcid":false,"given":"Yu","family":"Xia","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Melanie","family":"Holmgren","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chika","family":"Fujii","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3216-5574","authenticated-orcid":false,"given":"Saravanan","family":"Raju","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gue Su","family":"Chang","sequence":"additional","affiliation":[{"name":"McDonnell Genome Institute, Washington University School of Medicine, St Louis, MO; and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masahiro","family":"Iwamoto","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, University of Maryland, Baltimore, MD"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7489-1051","authenticated-orcid":false,"given":"Takeshi","family":"Egawa","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology and"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"234","reference":[{"issue":"6248","key":"2021121616405679200_B1","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1126\/science.aac4919","article-title":"HUMORAL IMMUNITY. 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