A cyclin-D1 interaction with BAX underlies its oncogenic role and potential as a therapeutic target in mantle cell lymphoma

Elena Beltran, Vicente Fresquet, Javier Martinez-Useros, Jose A. Richter-Larrea, Ainara Sagardoy, Izaskun Sesma, Luciana L. Almada, Santiago Montes-Moreno, Reiner Siebert, Stefan Gesk, Maria J. Calasanz, Raquel Malumbres, Melissa Rieger, Felipe Prosper, Izidore S. Lossos, Miguel Angel Piris, Martin E. Fernandez-Zapico, Jose A. Martinez-Climent

Research output: Contribution to journalArticle

36 Scopus citations

Abstract

The chromosomal translocation t(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-driven mouse model in which cyclin-D1 expression can be regulated externally. These mice developed cyclin-D1-expressing 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 1-S transition, sequestrates the proapoptotic protein BAX in the cytoplasm, thereby favoring BCL2's 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-expressing 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-expressing tumors.

Original languageEnglish (US)
Pages (from-to)12461-12466
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number30
DOIs
StatePublished - Jul 26 2011

Keywords

  • ABT-737
  • Cyclin-D1 inhibitor drugs
  • Mouse model of MCL
  • Oncogene addiction
  • Targeted therapy

ASJC Scopus subject areas

  • General

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    Beltran, E., Fresquet, V., Martinez-Useros, J., Richter-Larrea, J. A., Sagardoy, A., Sesma, I., Almada, L. L., Montes-Moreno, S., Siebert, R., Gesk, S., Calasanz, M. J., Malumbres, R., Rieger, M., Prosper, F., Lossos, I. S., Piris, M. A., Fernandez-Zapico, M. E., & Martinez-Climent, J. A. (2011). A cyclin-D1 interaction with BAX underlies its oncogenic role and potential as a therapeutic target in mantle cell lymphoma. Proceedings of the National Academy of Sciences of the United States of America, 108(30), 12461-12466. https://doi.org/10.1073/pnas.1018941108