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CLL exhibits remarkable clinical heterogeneity, with some patients presenting with indolent disease and others progressing rapidly to aggressive CLL. The significant heterogeneity of CLL underscores the importance of identifying novel prognostic markers. Recently, the RAS-related gene RRAS2 has emerged as both a driver oncogene and a potential marker for CLL progression, with higher RRAS2 expression associated with poorer disease prognosis. Although missense somatic mutations in the coding sequence of RRAS2 have not been described in CLL, this study reports the frequent detection of three somatic mutations in the 3\u2032 untranslated region (3\u2032UTR) affecting positions +26, +53, and +180 downstream of the stop codon in the mRNA. An inverse relationship was observed between these three somatic mutations and RRAS2 mRNA expression, which correlated with lower blood lymphocytosis. These findings highlight the importance of RRAS2 overexpression in CLL development and prognosis and point to somatic mutations in its 3\u2032UTR as novel mechanistic clues. Our results may contribute to the development of targeted therapeutic strategies and improved risk stratification for CLL patients.<\/jats:p>","DOI":"10.3390\/cells12232687","type":"journal-article","created":{"date-parts":[[2023,11,22]],"date-time":"2023-11-22T10:41:51Z","timestamp":1700649711000},"page":"2687","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Characterization of Three Somatic Mutations in the 3\u2032UTR of RRAS2 and Their Inverse Correlation with Lymphocytosis in Chronic Lymphocytic Leukemia"],"prefix":"10.3390","volume":"12","author":[{"given":"Marta","family":"Lacuna","sequence":"first","affiliation":[{"name":"Immune System Development and Function Program, Centro Biolog\u00eda Molecular Severo Ochoa, Consejo Superior de Investigaciones Cient\u00edficas (CSIC)-Universidad Aut\u00f3noma de Madrid, 28049 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alejandro M.","family":"Hortal","sequence":"additional","affiliation":[{"name":"Immune System Development and Function Program, Centro Biolog\u00eda Molecular Severo Ochoa, Consejo Superior de Investigaciones Cient\u00edficas (CSIC)-Universidad Aut\u00f3noma de Madrid, 28049 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3701-7901","authenticated-orcid":false,"given":"Claudia","family":"Cifuentes","sequence":"additional","affiliation":[{"name":"Immune System Development and Function Program, Centro Biolog\u00eda Molecular Severo Ochoa, Consejo Superior de Investigaciones Cient\u00edficas (CSIC)-Universidad Aut\u00f3noma de Madrid, 28049 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tania","family":"Gonzalo","sequence":"additional","affiliation":[{"name":"Immune System Development and Function Program, Centro Biolog\u00eda Molecular Severo Ochoa, Consejo Superior de Investigaciones Cient\u00edficas (CSIC)-Universidad Aut\u00f3noma de Madrid, 28049 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3819-4846","authenticated-orcid":false,"given":"Miguel","family":"Alcoceba","sequence":"additional","affiliation":[{"name":"Departamento de Hematolog\u00eda, Hospital Universitario de Salamanca (HUS-IBSAL), 37007 Salamanca, Spain"},{"name":"Centro de Investigaci\u00f3n del C\u00e1ncer, Instituto de Biolog\u00eda Molecular y Celular del C\u00e1ncer and Centro de Investigaci\u00f3n Biom\u00e9dica en Red de C\u00e1ncer, CSIC, Universidad de Salamanca, 37007 Salamanca, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3569-0139","authenticated-orcid":false,"given":"Miguel","family":"Bastos","sequence":"additional","affiliation":[{"name":"Departamento de Hematolog\u00eda, Hospital Universitario de Salamanca (HUS-IBSAL), 37007 Salamanca, Spain"},{"name":"Centro de Investigaci\u00f3n del C\u00e1ncer, Instituto de Biolog\u00eda Molecular y Celular del C\u00e1ncer and Centro de Investigaci\u00f3n Biom\u00e9dica en Red de C\u00e1ncer, CSIC, Universidad de Salamanca, 37007 Salamanca, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9398-6072","authenticated-orcid":false,"given":"Xos\u00e9 R.","family":"Bustelo","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n del C\u00e1ncer, Instituto de Biolog\u00eda Molecular y Celular del C\u00e1ncer and Centro de Investigaci\u00f3n Biom\u00e9dica en Red de C\u00e1ncer, CSIC, Universidad de Salamanca, 37007 Salamanca, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcos","family":"Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Departamento de Hematolog\u00eda, Hospital Universitario de Salamanca (HUS-IBSAL), 37007 Salamanca, Spain"},{"name":"Centro de Investigaci\u00f3n del C\u00e1ncer, Instituto de Biolog\u00eda Molecular y Celular del C\u00e1ncer and Centro de Investigaci\u00f3n Biom\u00e9dica en Red de C\u00e1ncer, CSIC, Universidad de Salamanca, 37007 Salamanca, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Balbino","family":"Alarc\u00f3n","sequence":"additional","affiliation":[{"name":"Immune System Development and Function Program, Centro Biolog\u00eda Molecular Severo Ochoa, Consejo Superior de Investigaciones Cient\u00edficas (CSIC)-Universidad Aut\u00f3noma de Madrid, 28049 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1016\/j.critrevonc.2007.04.008","article-title":"Chronic Lymphocytic Leukemia","volume":"64","author":"Ghia","year":"2007","journal-title":"Crit. 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