title: A cyclin-D1 interaction with BAX underlies its oncogenic role and potential as a therapeutic target in mantle cell lymphoma.
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.
authors: Center for Applied Medical Research, University of Navarra, Pamplona, Spain.
authors: Elena
authors: E
authors: Beltran
authors: Vicente
authors: V
authors: Fresquet
authors: Javier
authors: J
authors: Martinez-Useros
authors: Jose A
authors: JA
authors: Richter-Larrea
authors: Ainara
authors: A
authors: Sagardoy
authors: Izaskun
authors: I
authors: Sesma
authors: Luciana L
authors: LL
authors: Almada
authors: Santiago
authors: S
authors: Montes-Moreno
authors: Reiner
authors: R
authors: Siebert
authors: Stefan
authors: S
authors: Gesk
authors: Maria J
authors: MJ
authors: Calasanz
authors: Raquel
authors: R
authors: Malumbres
authors: Melissa
authors: M
authors: Rieger
authors: Felipe
authors: F
authors: Prosper
authors: Izidore S
authors: IS
authors: Lossos
authors: Miguel Angel
authors: MA
authors: Piris
authors: Martin E
authors: ME
authors: Fernandez-Zapico
authors: Jose A
authors: JA
authors: Martinez-Climent
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001713:Biphenyl Compounds / Q000494:pharmacology; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002470:Cell Survival; D019938:Cyclin D1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005784:Gene Amplification; D019254:Genes, bcl-2; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000209:etiology / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D051379:Mice; D009596:Nitrophenols / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D051028:bcl-2-Associated X Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: C501332:ABT-737; D000970:Antineoplastic Agents; C494826:BAX protein, human; C494827:Bax protein, mouse; D001713:Biphenyl Compounds; C530104:CCND1 protein, human; C530105:Ccnd1 protein, mouse; D009596:Nitrophenols; D010879:Piperazines; D013449:Sulfonamides; D051028:bcl-2-Associated X Protein; D019938:Cyclin D1