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Here, we report that <jats:italic>Gprasp1<\/jats:italic> and <jats:italic>Gprasp2<\/jats:italic>\u2010deficient B\u2010cells accumulate in the GC and show transcriptional abnormalities, affecting the mechanisms controlling <jats:italic>Aicda<\/jats:italic> expression and exposing them to excessive somatic hypermutation. Consequently, about 30% of mice transplanted with <jats:italic>Gprasp<\/jats:italic>\u2010deficient hematopoietic stem and progenitor cells developed a biologically aggressive and fatal B\u2010cell hyperproliferative disease by 20\u201350 weeks posttransplant. Histological and molecular profiling reveal that <jats:italic>Gprasp1\u2010<\/jats:italic> and <jats:italic>Gprasp2\u2010<\/jats:italic>deficient neoplasms morphologically resemble human high\u2010grade B\u2010cell lymphomas of germinal center origin with shared morphologic features of both Burkitt Lymphoma (BL) and diffuse large B\u2010cell lymphoma (DLBCL), and molecular features consistent with DLBCL, as well as elevated mutational burden and heterogenous transcriptional and mutational signature. Thus, reduced <jats:italic>Gprasp1<\/jats:italic> and <jats:italic>Gprasp2<\/jats:italic> gene expression perturbs B\u2010cell maturation and increases the risk of B\u2010cell neoplasms of germinal center origin. As this model recapitulates the essential features of the heterogenous group of human hematopoietic malignancies, it could be a powerful tool to interrogate the mechanisms of lymphomagenesis for these cancers.<\/jats:p>","DOI":"10.1002\/hem3.70037","type":"journal-article","created":{"date-parts":[[2024,10,30]],"date-time":"2024-10-30T15:02:31Z","timestamp":1730300551000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["GPRASP protein deficiency triggers lymphoproliferative disease by affecting B\u2010cell differentiation"],"prefix":"10.1002","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8539-6160","authenticated-orcid":false,"given":"Antonio","family":"Morales\u2010Hern\u00e1ndez","sequence":"first","affiliation":[{"name":"Department of Periodontics and Oral Medicine, School of Dentistry University of Michigan Ann Arbor Michigan 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