{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T19:34:26Z","timestamp":1792092866625,"version":"4.4.0"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,3,20]],"date-time":"2023-03-20T00:00:00Z","timestamp":1679270400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002923","name":"Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002923","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003074","name":"Agencia Nacional de Promoci\u00f3n Cient\u00edfica y Tecnol\u00f3gica","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003074","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:p>The treatment of chronic lymphocytic leukemia (CLL) patients with venetoclax-based regimens has demonstrated efficacy and a safety profile, but the emergence of resistant cells and disease progression is a current complication. Therapeutic target of sphingosine kinases (SPHK) 1 and 2 has opened new opportunities in the treatment combinations of cancer patients. We previously reported that the dual SPHK1\/2 inhibitor, SKI-II enhanced the <jats:italic>in vitro<\/jats:italic> cell death triggered by fludarabine, bendamustine or ibrutinib and reduced the activation and proliferation of chronic lymphocytic leukemia (CLL) cells. Since we previously showed that autologous activated T cells from CLL patients favor the activation of CLL cells and the generation of venetoclax resistance due to the upregulation of BCL-XL and MCL-1, we here aim to determine whether SPHK inhibitors affect this process. To this aim we employed the dual SPHK1\/2 inhibitor SKI-II and opaganib, a SPHK2 inhibitor that is being studied in clinical trials. We found that SPHK inhibitors reduce the activation of CLL cells and the generation of venetoclax resistance induced by activated T cells mainly due to a reduced upregulation of BCL-XL. We also found that SPHK2 expression was enhanced in CLL cells by activated T cells of the same patient and the presence of venetoclax selects resistant cells with high levels of SPHK2. Of note, SPHK inhibitors were able to re-sensitize already resistant CLL cells to a second venetoclax treatment. Our results highlight the therapeutic potential of SPHK inhibitors in combination with venetoclax as a promising treatment option for the patients.<\/jats:p>","DOI":"10.3389\/fonc.2023.1143881","type":"journal-article","created":{"date-parts":[[2023,3,20]],"date-time":"2023-03-20T05:12:49Z","timestamp":1679289169000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Venetoclax resistance induced by activated T cells can be counteracted by sphingosine kinase inhibitors in chronic lymphocytic leukemia"],"prefix":"10.3389","volume":"13","author":[{"given":"Valeria J.","family":"Sarapura Martinez","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brenda","family":"Buonincontro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Cassarino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juliana","family":"Bernatowiez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Colado","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregorio","family":"Cordini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria del Rosario","family":"Custidiano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolina","family":"Mahuad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel A.","family":"Pavlovsky","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raimundo F.","family":"Bezares","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicol\u00e1s O.","family":"Favale","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00f3nica","family":"Vermeulen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mercedes","family":"Borge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mirta","family":"Giordano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Romina","family":"Gamberale","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,3,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1513257","article-title":"Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia","volume":"374","author":"Roberts","year":"2016","journal-title":"N Engl J Med"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1053\/j.seminhematol.2014.05.008","article-title":"Targeting BCL2 for the treatment of lymphoid malignancies","volume":"51","author":"Anderson","year":"2014","journal-title":"Semin Hematol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1815281","article-title":"Venetoclax and obinutuzumab in patients with CLL and coexisting conditions","volume":"380","author":"Fischer","year":"2019","journal-title":"N Engl J Med"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1713976","article-title":"Venetoclax-rituximab in relapsed or refractory chronic lymphocytic leukemia","volume":"378","author":"Seymour","year":"2018","journal-title":"N Engl J Med"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2018.193615","article-title":"Real-world outcomes and management strategies for venetoclax-treated chronic lymphocytic leukemia patients in the united states","volume":"103","author":"Mato","year":"2018","journal-title":"Haematologica"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1900574","article-title":"Ibrutinib and venetoclax for first-line treatment of CLL","volume":"380","author":"Jain","year":"2019","journal-title":"N Engl J Med"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2019004205","article-title":"Multiple BCL2 mutations cooccurring with Gly101Val emerge in chronic lymphocytic leukemia progression on venetoclax","volume":"135","author":"Blombery","year":"2020","journal-title":"Blood"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2018.00458","article-title":"Hematologic tumor cell resistance to the BCL-2 inhibitor venetoclax: A product of its microenvironment","volume":"8","author":"Leverson","year":"2018","journal-title":"Front Oncol"},{"key":"B9","doi-asserted-by":"publisher","first-page":":2918-2926","DOI":"10.1182\/blood.2019004326","article-title":"Changes in bcl-2 members after ibrutinib or venetoclax uncover functional hierarchy in determining resistance to venetoclax in CLL","volume":"136","author":"Haselager","year":"2020","journal-title":"Blood"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2020003944","article-title":"Extrinsic interactions in the microenvironment in vivo activate an antiapoptotic multidrug-resistant phenotype in CLL","volume":"5","author":"Jayappa","year":"2021","journal-title":"Blood advances."},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1007\/s00262-021-03043-x","article-title":"Venetoclax-resistant CLL cells show a highly activated and proliferative phenotype","volume":"71","author":"Elias","year":"2022","journal-title":"Cancer Immunol Immunother."},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2018.188680","article-title":"Autologous T-cell activation fosters ABT-199 resistance in chronic lymphocytic leukemia: rationale for a combined therapy with SYK inhibitors and anti-CD20 monoclonal antibodies","volume":"103","author":"Elias","year":"2018","journal-title":"Haematologica"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2015-10-675009","article-title":"BCR signaling inhibitors differ in their ability to overcome mcl-1-mediated resistance of CLL b cells to ABT-199","volume":"127","author":"Bojarczuk","year":"2016","journal-title":"Blood"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2015-12-687814","article-title":"High-content screening identifies kinase inhibitors that overcome venetoclax resistance in activated CLL cells","volume":"128","author":"Oppermann","year":"2016","journal-title":"Blood"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2015.124560","article-title":"Resistance to ABT-199 induced by microenvironmental signals in chronic lymphocytic leukemia can be counteracted by CD20 antibodies or kinase inhibitors","volume":"100","author":"Thijssen","year":"2015","journal-title":"Haematologica"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/nri2974","article-title":"The outs and the ins of sphingosine-1-phosphate in immunity","volume":"11","author":"Spiegel","year":"2011","journal-title":"Nat Rev Immunol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2016.00218","article-title":"Sphingosine-1 phosphate: A new modulator of immune plasticity in the tumor microenvironment","volume":"6","author":"Rodriguez","year":"2016","journal-title":"Front Oncol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbalip.2012.07.002","article-title":"Targeting the sphingosine kinase\/sphingosine 1-phosphate pathway in disease: review of sphingosine kinase inhibitors","volume":"1831","author":"Orr Gandy","year":"2013","journal-title":"Biochim Biophys Acta"},{"key":"B19","doi-asserted-by":"publisher","first-page":"e257-60","DOI":"10.3324\/haematol.2017.167353","article-title":"Sphingosine kinase 1 participates in the activation, proliferation and survival of chronic lymphocytic leukemia cells","volume":"102","author":"Almejun","year":"2017","journal-title":"Haematologica"},{"key":"B20","doi-asserted-by":"publisher","first-page":"109806","DOI":"10.1016\/j.cellsig.2020.109806","article-title":"Structure-function analysis of lipid substrates and inhibitors of sphingosine kinases","volume":"76","author":"Adams","year":"2020","journal-title":"Cell Signal"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.14119","article-title":"SphK1 inhibitor potentiates the anti-cancer effect of EGCG on leukaemia cells","volume":"178","author":"Tsukamoto","year":"2017","journal-title":"Br J Haematol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.2147\/DDDT.S367612","article-title":"Recent progress in the development of opaganib for the treatment of covid-19","volume":"16","author":"Smith","year":"2022","journal-title":"Drug design Dev Ther"},{"key":"B23","doi-asserted-by":"publisher","first-page":":10767-91","DOI":"10.3390\/ijms221910767","article-title":"The sphingosine kinase 2 inhibitor ABC294640 restores the sensitivity of BRAFV600E mutant colon cancer cells to vemurafenib by reducing AKT-mediated expression of nucleophosmin and translationally-controlled tumour protein","volume":"22","author":"Grbcic","year":"2021","journal-title":"Int J Mol Sci"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(17)30012-8","article-title":"Venetoclax plus rituximab in relapsed or refractory chronic lymphocytic leukaemia: a phase 1b study","volume":"18","author":"Seymour","year":"2017","journal-title":"Lancet Oncol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-16-2363","article-title":"A phase I study of ABC294640, a first-in-Class sphingosine kinase-2 inhibitor, in patients with advanced solid tumors","volume":"23","author":"Britten","year":"2017","journal-title":"Clin Cancer Res"},{"key":"B26","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1016\/bs.acr.2018.04.015","article-title":"Targeting sphingosine kinases for the treatment of cancer","volume":"140","author":"Lewis","year":"2018","journal-title":"Adv Cancer Res"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1007\/s00262-012-1320-7","article-title":"CXCL12 is a costimulator for CD4+ T cell activation and proliferation in chronic lymphocytic leukemia patients","volume":"62","author":"Borge","year":"2013","journal-title":"Cancer Immunol Immunother."},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-05-284984","article-title":"The lymph node microenvironment promotes b-cell receptor signaling, NF-kappaB activation, and tumor proliferation in chronic lymphocytic leukemia","volume":"117","author":"Herishanu","year":"2011","journal-title":"Blood"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2017.11","article-title":"Direct in vivo evidence for increased proliferation of CLL cells in lymph nodes compared to bone marrow and peripheral blood","volume":"31","author":"Herndon","year":"2017","journal-title":"Leukemia"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2019000360","article-title":"Distinct immune composition in lymph node and peripheral blood of CLL patients is reshaped during venetoclax treatment","volume":"3","author":"de Weerdt","year":"2019","journal-title":"Blood advances."},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2016-06-720433","article-title":"Targeting sphingosine kinase 1 induces MCL1-dependent cell death in acute myeloid leukemia","volume":"129","author":"Powell","year":"2017","journal-title":"Blood"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1210587","article-title":"Sphingosine kinase-1 mediates BCR\/ABL-induced upregulation of mcl-1 in chronic myeloid leukemia cells","volume":"26","author":"Li","year":"2007","journal-title":"Oncogene"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.16530","article-title":"Sphingosine kinase-2 is overexpressed in large granular lymphocyte leukaemia and promotes survival through mcl-1","volume":"190","author":"LeBlanc","year":"2020","journal-title":"Br J Haematol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2014-03-559385","article-title":"Inhibition of sphingosine kinase 2 downregulates the expression of c-myc and mcl-1 and induces apoptosis in multiple myeloma","volume":"124","author":"Venkata","year":"2014","journal-title":"Blood"},{"key":"B35","doi-asserted-by":"publisher","first-page":"1284","DOI":"10.1182\/blood-2019-131336","article-title":"MCL-1 and PKA\/AMPK axis fuel venetoclax resistance in lymphoid cancers","volume":"134","author":"Liu","year":"2019","journal-title":"Blood"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1038\/s41418-020-00692-w","article-title":"Regulation of bcl-XL by non-canonical NF-kappaB in the context of CD40-induced drug resistance in CLL","volume":"28","author":"Haselager","year":"2021","journal-title":"Cell Death differentiation."},{"key":"B37","doi-asserted-by":"publisher","first-page":"1879","DOI":"10.1016\/j.celrep.2019.07.044","article-title":"Pro-survival lipid sphingosine-1-Phosphate metabolically programs T cells to limit anti-tumor activity","volume":"28","author":"Chakraborty","year":"2019","journal-title":"Cell Rep"},{"key":"B38","doi-asserted-by":"publisher","first-page":"13233","DOI":"10.1038\/s41598-018-31666-1","article-title":"Sphingosine kinases promote IL-17 expression in human T lymphocytes","volume":"8","author":"Barra","year":"2018","journal-title":"Sci Rep"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2016030306","article-title":"Sphingosine kinase 2 deficiency attenuates kidney fibrosis via IFN-gamma","volume":"28","author":"Bajwa","year":"2017","journal-title":"J Am Soc Nephrol JASN."},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1038\/s41375-022-01543-y","article-title":"High expression level of ROR1 and ROR1-signaling associates with venetoclax resistance in chronic lymphocytic leukemia","volume":"36","author":"Ghia","year":"2022","journal-title":"Leukemia"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2020008502","article-title":"How I treat chronic lymphocytic leukemia after venetoclax","volume":"138","author":"Lew","year":"2021","journal-title":"Blood"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.2119\/molmed.2011.00360","article-title":"Intraclonal complexity in chronic lymphocytic leukemia: fractions enriched in recently born\/divided and older\/quiescent cells","volume":"17","author":"Calissano","year":"2011","journal-title":"Mol Med"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2009.03.018","article-title":"Glucosylceramide synthase inhibitors sensitise CLL cells to cytotoxic agents without reversing p-gp functional activity","volume":"609","author":"Gerrard","year":"2009","journal-title":"Eur J Pharmacol"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2023.1143881\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,3,20]],"date-time":"2023-03-20T05:12:53Z","timestamp":1679289173000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2023.1143881\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,20]]},"references-count":43,"alternative-id":["10.3389\/fonc.2023.1143881"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2023.1143881","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,20]]},"article-number":"1143881"}}