{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T06:05:36Z","timestamp":1791353136439,"version":"4.3.1"},"reference-count":28,"publisher":"National Academy of Sciences","issue":"30","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2011,7,26]]},"abstract":"<jats:p>\n                    The chromosomal translocation\n                    <jats:italic>t<\/jats:italic>\n                    (11;14)(q13;q32) leading to cyclin-D1 overexpression plays an essential role in the development of mantle cell lymphoma (MCL), an aggressive tumor that remains incurable with current treatment strategies. Cyclin-D1 has been postulated as an effective therapeutic target, but the evaluation of this target has been hampered by our incomplete understanding of its oncogenic functions and by the lack of valid MCL murine models. To address these issues, we generated a cyclin-D1\u2013driven mouse model in which cyclin-D1 expression can be regulated externally. These mice developed cyclin-D1\u2013expressing lymphomas capable of recapitulating features of human MCL. We found that cyclin-D1 inactivation was not sufficient to induce lymphoma regression in vivo; however, using a combination of in vitro and in vivo assays, we identified a novel prosurvival cyclin-D1 function in MCL cells. Specifically, we found that cyclin-D1, besides increasing cell proliferation through deregulation of the cell cycle at the G\n                    <jats:sub>1<\/jats:sub>\n                    \u2013S transition, sequestrates the proapoptotic protein BAX in the cytoplasm, thereby favoring BCL2\u2019s antiapoptotic function. Accordingly, cyclin-D1 inhibition sensitized the lymphoma cells to apoptosis through BAX release. Thus, genetic or pharmacologic targeting of cyclin-D1 combined with a proapoptotic BH3 mimetic synergistically killed the cyclin-D1\u2013expressing murine lymphomas, human MCL cell lines, and primary lymphoma cells. Our study identifies a role of cyclin-D1 in deregulating apoptosis in MCL cells, and highlights the potential benefit of simultaneously targeting cyclin-D1 and survival pathways in patients with MCL. This effective combination therapy also might be exploited in other cyclin-D1\u2013expressing tumors.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1018941108","type":"journal-article","created":{"date-parts":[[2011,7,12]],"date-time":"2011-07-12T02:10:10Z","timestamp":1310436610000},"page":"12461-12466","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":49,"title":["A cyclin-D1 interaction with BAX underlies its oncogenic role and potential as a therapeutic target in mantle cell lymphoma"],"prefix":"10.1073","volume":"108","author":[{"given":"Elena","family":"Beltran","sequence":"first","affiliation":[{"name":"Oncology Division, Center for Applied Medical Research, University of Navarra, 31008 Pamplona, Spain;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vicente","family":"Fresquet","sequence":"additional","affiliation":[{"name":"Oncology Division, Center for Applied Medical Research, University of Navarra, 31008 Pamplona, Spain;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javier","family":"Martinez-Useros","sequence":"additional","affiliation":[{"name":"Oncology Division, Center for Applied Medical Research, University of Navarra, 31008 Pamplona, Spain;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose A.","family":"Richter-Larrea","sequence":"additional","affiliation":[{"name":"Oncology Division, Center for Applied Medical Research, University of Navarra, 31008 Pamplona, Spain;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ainara","family":"Sagardoy","sequence":"additional","affiliation":[{"name":"Oncology Division, Center for Applied Medical Research, University of Navarra, 31008 Pamplona, Spain;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Izaskun","family":"Sesma","sequence":"additional","affiliation":[{"name":"Oncology Division, Center for Applied Medical Research, University of Navarra, 31008 Pamplona, Spain;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luciana L.","family":"Almada","sequence":"additional","affiliation":[{"name":"Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, MN 55905;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Santiago","family":"Montes-Moreno","sequence":"additional","affiliation":[{"name":"Molecular Pathology Program, National Cancer Research Center, 28029 Madrid, Spain;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reiner","family":"Siebert","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Christian-Albrechts University Kiel and University Hospital Schleswig-Holstein, Campus Kiel, 24118 Kiel, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Gesk","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Christian-Albrechts University Kiel and University Hospital Schleswig-Holstein, Campus Kiel, 24118 Kiel, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria J.","family":"Calasanz","sequence":"additional","affiliation":[{"name":"Department of Genetics, University of Navarra, 31008 Pamplona, Spain;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raquel","family":"Malumbres","sequence":"additional","affiliation":[{"name":"Oncology Division, Center for Applied Medical Research, University of Navarra, 31008 Pamplona, Spain;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa","family":"Rieger","sequence":"additional","affiliation":[{"name":"Oncology Division, Center for Applied Medical Research, University of Navarra, 31008 Pamplona, Spain;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felipe","family":"Prosper","sequence":"additional","affiliation":[{"name":"Oncology Division, Center for Applied Medical Research, University of Navarra, 31008 Pamplona, Spain;"},{"name":"Department of Hematology and Cell Therapy, Clinica Universidad de Navarra, 31008 Pamplona, Spain; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Izidore S.","family":"Lossos","sequence":"additional","affiliation":[{"name":"Division of Hematology-Oncology, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136-1002"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel Angel","family":"Piris","sequence":"additional","affiliation":[{"name":"Molecular Pathology Program, National Cancer Research Center, 28029 Madrid, Spain;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin E.","family":"Fernandez-Zapico","sequence":"additional","affiliation":[{"name":"Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, MN 55905;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose A.","family":"Martinez-Climent","sequence":"additional","affiliation":[{"name":"Oncology Division, Center for Applied Medical Research, University of Navarra, 31008 Pamplona, Spain;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2011,7,11]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1038\/modpathol.3880035","article-title":"The World Health Organization classification of hematological malignancies: Report of the Clinical Advisory Committee Meeting, Airlie House, Virginia, November 1997","volume":"13","author":"Harris NL","year":"2000","unstructured":"NL Harris, et al., The World Health Organization classification of hematological malignancies: Report of the Clinical Advisory Committee Meeting, Airlie House, Virginia, November 1997. 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