{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:37:12Z","timestamp":1760146632647,"version":"build-2065373602"},"reference-count":51,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2024,11,22]],"date-time":"2024-11-22T00:00:00Z","timestamp":1732233600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Initiative Krebsforschung","award":["UE71104037"],"award-info":[{"award-number":["UE71104037"]}]},{"name":"Fellinger Krebsforschung","award":["UE71104037"],"award-info":[{"award-number":["UE71104037"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Constitutively active NOTCH2 signaling is a hallmark in chronic lymphocytic leukemia (CLL). The precise underlying defect remains obscure. Here we show that the mRNA sequence coding for the NOTCH2 negative regulatory region (NRR) is consistently deleted in CLL cells. The most common NOTCH2\u0394NRR-DEL2 deletion is associated with two intronic single nucleotide variations (SNVs) which either create (CTTAT, G&gt;A for rs2453058) or destroy (CTCGT, A&gt;G for rs5025718) a putative splicing branch point sequence (BPS). Phylogenetic analysis demonstrates that rs2453058 is part of an ancient NOTCH2 gene variant (*1A01) which is associated with type 2 diabetes mellitus (T2DM) and is two times more frequent in Europeans than in East Asians, resembling the differences in CLL incidence. In contrast, rs5025718 belongs to a recent NOTCH2 variant (*1a4) that dominates the world outside Africa. Nanopore sequencing indicates that somatic reciprocal crossing over between rs2453058 (*1A01) and rs5025718 (*1a4) leads to recombined NOTCH2 alleles with altered BPS patterns in NOTCH2*1A01\/*1a4 CLL cases. This would explain the loss of the NRR domain by aberrant pre-mRNA splicing and consequently the NOTCH2 gain-of-function phenotype. Together, our findings suggest that somatic recombination of inherited NOTCH2 variants might be relevant to CLL etiology and may at least partly explain its geographical clustering.<\/jats:p>","DOI":"10.3390\/ijms252312581","type":"journal-article","created":{"date-parts":[[2024,11,22]],"date-time":"2024-11-22T12:07:32Z","timestamp":1732277252000},"page":"12581","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Somatic Recombination Between an Ancient and a Recent NOTCH2 Gene Variant Is Associated with the NOTCH2 Gain-of-Function Phenotype in Chronic Lymphocytic Leukemia"],"prefix":"10.3390","volume":"25","author":[{"given":"Rainer","family":"Hubmann","sequence":"first","affiliation":[{"name":"Department of Internal Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, 1090 Vienna, Austria"},{"name":"Comprehensive Cancer Center Vienna, Medical University of Vienna, 1090 Vienna, Austria"},{"name":"Austrian Red Cross, Blood Service for Vienna, Lower Austria and Burgenland, 1040 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martin","family":"Hilgarth","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-9196-2097","authenticated-orcid":false,"given":"Tamara","family":"L\u00f6wenstern","sequence":"additional","affiliation":[{"name":"Institute of Medical Genetics, Center for Pathobiochemistry and Genetics, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Lienhard","sequence":"additional","affiliation":[{"name":"Austrian Red Cross, Blood Service for Vienna, Lower Austria and Burgenland, 1040 Vienna, 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Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christof","family":"Jungbauer","sequence":"additional","affiliation":[{"name":"Austrian Red Cross, Blood Service for Vienna, Lower Austria and Burgenland, 1040 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0456-5095","authenticated-orcid":false,"given":"Peter","family":"Valent","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, 1090 Vienna, Austria"},{"name":"Comprehensive Cancer Center Vienna, Medical University of Vienna, 1090 Vienna, Austria"},{"name":"Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Philipp B.","family":"Staber","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, 1090 Vienna, Austria"},{"name":"Comprehensive Cancer Center Vienna, Medical University of Vienna, 1090 Vienna, Austria"},{"name":"Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Medhat","family":"Shehata","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, 1090 Vienna, Austria"},{"name":"Comprehensive Cancer Center Vienna, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9826-1062","authenticated-orcid":false,"given":"Ulrich","family":"J\u00e4ger","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, 1090 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