{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,7]],"date-time":"2025-11-07T09:42:38Z","timestamp":1762508558431,"version":"build-2065373602"},"reference-count":30,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T00:00:00Z","timestamp":1762387200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background\/Objectives: NOTCH1 is frequently mutated in chronic lymphocytic leukemia (CLL) and is a marker of poor prognosis. In addition to NOTCH1, mutations in the NOTCH1 regulatory pathway including SPEN have been described in a limited number of CLL cases and others have suggested that these mutations are also associated with adverse patient outcomes Methods: In this study, 1617 CLL cases were assessed using targeted sequencing and a 29-gene panel and the results were correlated with prognosis. Results: SPEN mutations were detected in 48 (2.9%) CLL patients: 92.4% were deleterious (frameshift or truncating nonsense mutations) and the remaining (7.6%) were missense. Compared with SPEN wild type CLL patients, SPEN mutated patients had a statistically higher frequency of IGHV unmutated status (79.5% vs. 57.8%, p = 0.004), CD38 positivity (73.3% vs. 52.4%, p = 0.01), ZAP70 positivity (77.3% vs. 58.3%, p = 0.01) and trisomy 12 (43.5% vs. 13.7%, p &lt; 0.001). The most common gene mutations co-occurring with SPEN mutations were as follows: NOTCH1 (43.7%), TP53 (22.9%), BIRC3 (12.5%), SF3B1 (10.4%), XPO1 (8.3%), MUC2 (6.2%), ATM (4.2%), FBXW7 (4.2%), and BTK (4.2%). Patients with SPEN mutated CLL had a significantly shorter time-to-first treatment compared to CLL patients with wild type SPEN (2.5 vs. 4.07 years, p = 0.01). The finding of shorter time-to-first treatment in SPEN mutated CLL patients was not maintained in a multivariable analysis. IGHV unmutated status, TP53 disruption, and trisomy 12 remained independently predictive of a shorter time-to-first treatment in a multivariable analysis. Conclusions: These data show that SPEN mutations in CLL are associated with adverse prognostic impact and should be included in sequencing assays performed for the prognostic workup of CLL patients.<\/jats:p>","DOI":"10.3390\/cancers17213586","type":"journal-article","created":{"date-parts":[[2025,11,7]],"date-time":"2025-11-07T09:14:45Z","timestamp":1762506885000},"page":"3586","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Mutational Landscape and Clinical Impact of SPEN Mutations in Patients with Chronic Lymphocytic Leukemia"],"prefix":"10.3390","volume":"17","author":[{"given":"Priyatharsini","family":"Nirmalanantham","sequence":"first","affiliation":[{"name":"Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5304-7828","authenticated-orcid":false,"given":"Andr\u00e9s E.","family":"Quesada","sequence":"additional","affiliation":[{"name":"Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4391-1811","authenticated-orcid":false,"given":"Anindita","family":"Ghosh","sequence":"additional","affiliation":[{"name":"Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pei","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6822-7880","authenticated-orcid":false,"given":"Chi Y.","family":"Ok","sequence":"additional","affiliation":[{"name":"Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0433-8626","authenticated-orcid":false,"given":"Richard K.","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1780-5959","authenticated-orcid":false,"given":"Hong","family":"Fang","sequence":"additional","affiliation":[{"name":"Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sofia","family":"Garces","sequence":"additional","affiliation":[{"name":"Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7829-5249","authenticated-orcid":false,"given":"Rashmi","family":"Kanagal-Shamanna","sequence":"additional","affiliation":[{"name":"Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8980-3202","authenticated-orcid":false,"given":"Sanam","family":"Loghavi","sequence":"additional","affiliation":[{"name":"Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark J.","family":"Routbort","sequence":"additional","affiliation":[{"name":"Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6630-4128","authenticated-orcid":false,"given":"Cameron Cheng","family":"Yin","sequence":"additional","affiliation":[{"name":"Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wang","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah","family":"Pasyar","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4534-2042","authenticated-orcid":false,"given":"Roland","family":"Bassett","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1338-7107","authenticated-orcid":false,"given":"Siba","family":"El Hussein","sequence":"additional","affiliation":[{"name":"Department Pathology, The University of Vermont Medical Center, Burlington, VT 05401, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nitin","family":"Jain","sequence":"additional","affiliation":[{"name":"Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan","family":"Burger","sequence":"additional","affiliation":[{"name":"Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William G.","family":"Wierda","sequence":"additional","affiliation":[{"name":"Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sa","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carlos","family":"Bueso-Ramos","sequence":"additional","affiliation":[{"name":"Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Keyur P.","family":"Patel","sequence":"additional","affiliation":[{"name":"Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6577-8006","authenticated-orcid":false,"given":"Leonard Jeffrey","family":"Medeiros","sequence":"additional","affiliation":[{"name":"Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3791-3204","authenticated-orcid":false,"given":"Fatima Zahra","family":"Jelloul","sequence":"additional","affiliation":[{"name":"Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1056\/NEJMra041720","article-title":"Chronic lymphocytic leukemia","volume":"352","author":"Chiorazzi","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"16096","DOI":"10.1038\/nrdp.2016.96","article-title":"Chronic lymphocytic leukaemia","volume":"3","author":"Kipps","year":"2017","journal-title":"Nat. Rev. Dis. Prim."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1002\/ajh.24282","article-title":"Chronic lymphocytic leukemia (CLL)-Then and now","volume":"91","author":"Rai","year":"2016","journal-title":"Am. J. Hematol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2265","DOI":"10.1080\/10428194.2022.2090551","article-title":"CD38 as a multifaceted immunotherapeutic target in CLL","volume":"63","author":"Paulus","year":"2022","journal-title":"Leuk. Lymphoma."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1518","DOI":"10.1038\/modpathol.2010.131","article-title":"Immunohistochemical detection of ZAP70 in chronic lymphocytic leukemia predicts immunoglobulin heavy chain gene mutation status and time to progression","volume":"23","author":"Admirand","year":"2010","journal-title":"Mod. Pathol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1599","DOI":"10.3324\/haematol.2014.107326","article-title":"Chronic lymphocytic leukemia in the elderly: Clinico-biological features, outcomes, and proposal of a prognostic model","volume":"99","author":"Baumann","year":"2014","journal-title":"Haematologica"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1038\/nrc.2016.8","article-title":"The molecular pathogenesis of chronic lymphocytic leukaemia","volume":"16","author":"Fabbri","year":"2016","journal-title":"Nat. Rev. Cancer"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2122","DOI":"10.1182\/blood-2015-07-659144","article-title":"Clinical impact of clonal and subclonal TP53, SF3B1, BIRC3, NOTCH1, and ATM mutations in chronic lymphocytic leukemia","volume":"127","author":"Nadeu","year":"2016","journal-title":"Blood"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1182\/blood-2011-09-379966","article-title":"Mutations of NOTCH1 are an independent predictor of survival in chronic lymphocytic leukemia","volume":"119","author":"Rossi","year":"2012","journal-title":"Blood"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2497","DOI":"10.1056\/NEJMoa1109016","article-title":"SF3B1 and other novel cancer genes in chronic lymphocytic leukemia","volume":"365","author":"Wang","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1111\/bjh.14869","article-title":"MED12 mutations and NOTCH signaling in chronic lymphocytic leukaemia","volume":"179","author":"Wu","year":"2017","journal-title":"Br. J. Haematol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1379","DOI":"10.3324\/haematol.2019.217307","article-title":"Genomic alterations in high-risk chronic lymphocytic leukemia frequently affect cell cycle key regulators and NOTCH1-regulated transcription","volume":"105","author":"Edelmann","year":"2020","journal-title":"Haematologica"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Andreani, G., Carr\u00e0, G., Lingua, M.F., Maffeo, B., Brancaccio, M., Taulli, R., and Morotti, A. (2020). Tumor Suppressors in Chronic Lymphocytic Leukemia: From Lost Partners to Active Targets. Cancers, 12.","DOI":"10.3390\/cancers12030629"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1002\/ajh.24301","article-title":"Chronic lymphocytic leukemia: Time to go past genomics?","volume":"91","author":"Bernard","year":"2016","journal-title":"Am. J. Hematol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"E187","DOI":"10.1002\/ajh.26140","article-title":"Outcomes in CLL patients with NOTCH1 regulatory pathway mutations","volume":"96","author":"Helbig","year":"2021","journal-title":"Am. J. Hematol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1111\/bjh.16042","article-title":"Association of gene mutations with time-to-first treatment in 384 treatment-naive chronic lymphocytic leukaemia patients","volume":"187","author":"Hu","year":"2019","journal-title":"Br. J. Haematol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1038\/nature14666","article-title":"Non-coding recurrent mutations in chronic lymphocytic leukaemia","volume":"526","author":"Puente","year":"2015","journal-title":"Nature"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1111\/ejh.13550","article-title":"Predictive significance of selected gene mutations in relapsed and refractory chronic lymphocytic leukemia patients treated with ibrutinib","volume":"106","author":"Machnicki","year":"2021","journal-title":"Eur. J. Haematol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"830","DOI":"10.1182\/blood-2018-09-874529","article-title":"FBXW7 mutations reduce binding of NOTCH1, leading to cleaved NOTCH1 accumulation and target gene activation in CLL","volume":"133","author":"Close","year":"2019","journal-title":"Blood"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"E100","DOI":"10.1002\/ajh.26457","article-title":"Non-coding NOTCH1 mutations in chronic lymphocytic leukemia negatively impact prognosis","volume":"97","author":"Jelloul","year":"2022","journal-title":"Am. J. Hematol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"106827","DOI":"10.1016\/j.leukres.2022.106827","article-title":"Landscape of NOTCH1 mutations and co-occurring biomarker alterations in chronic lymphocytic leukemia","volume":"116","author":"Jelloul","year":"2022","journal-title":"Leuk. Res."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Baldoni, S., Del Papa, B., De Falco, F., Dorillo, E., Sorrentino, C., Rompietti, C., Adamo, F., Nogaratto, M., Cecchini, D., and Mondani, E. (2021). NOTCH1 Activation Negatively Impacts on Chronic Lymphocytic Leukemia Outcome and Is Not Correlated to the NOTCH1 and IGHV Mutational Status. Front. Oncolo., 11.","DOI":"10.3389\/fonc.2021.668573"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"E2911","DOI":"10.1073\/pnas.1702564114","article-title":"Common non-mutational NOTCH1 activation in chronic lymphocytic leukemia","volume":"114","author":"Fabbri","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2745","DOI":"10.1182\/blood-2017-09-806398","article-title":"iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL","volume":"131","author":"Hallek","year":"2018","journal-title":"Blood"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2854","DOI":"10.1182\/blood-2011-12-395673","article-title":"Disruption of BIRC3 associates with fludarabine chemorefractoriness in TP53 wild-type chronic lymphocytic leukemia","volume":"119","author":"Rossi","year":"2012","journal-title":"Blood"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"6904","DOI":"10.1182\/blood-2011-08-373159","article-title":"Mutations of the SF3B1 splicing factor in chronic lymphocytic leukemia: Association with progression and fludarabine-refractoriness","volume":"118","author":"Rossi","year":"2011","journal-title":"Blood"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Soussi, T., and Baliakas, P. (2022). Landscape of TP53 Alterations in Chronic Lymphocytic Leukemia via Data Mining Mutation Databases. Front. Oncol., 16.","DOI":"10.3389\/fonc.2022.808886"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"4191","DOI":"10.1182\/blood-2012-05-433540","article-title":"Monitoring chronic lymphocytic leukemia progression by whole genome sequencing reveals heterogeneous clonal evolution patterns","volume":"120","author":"Schuh","year":"2012","journal-title":"Blood"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1993","DOI":"10.1182\/blood-2007-07-099432","article-title":"Genomic complexity identifies patients with aggressive chronic lymphocytic leukemia","volume":"112","author":"Kujawski","year":"2008","journal-title":"Blood"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1403","DOI":"10.1182\/blood-2012-09-458265","article-title":"Integrated mutational and cytogenetic analysis identifies new prognostic subgroups in chronic lymphocytic leukemia","volume":"121","author":"Rossi","year":"2013","journal-title":"Blood"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/17\/21\/3586\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,7]],"date-time":"2025-11-07T09:26:30Z","timestamp":1762507590000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/17\/21\/3586"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,6]]},"references-count":30,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["cancers17213586"],"URL":"https:\/\/doi.org\/10.3390\/cancers17213586","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,6]]}}}