Inactivación terapéutica del oncogén ccnd1 en modelos celulares humanos y murinos de linfoma de células del manto

Résumé

Targeting CCND1 oncogene to treat Mantle Cell Lymphoma in human and mouse models ABSTRACT Mantle cell lymphoma (MCL) is initiated by cyclin-D1 activation followed by genetic changes involving survival and DNA-repair machineries. Because MCL is incurable with current treatments, the use of drugs targeting cyclin-D1 and/or other molecular pathways may be of clinical benefit. Here, we screened for predictors of response to target-directed therapies in human MCL-derived cell lines and in a human-like MCL mouse model generated by co-expressing cyclin-D1 and BCL2 in naïve B lymphocytes engrafted in immunodeficient RAG2-/-IL2c-/- mice. In these lymphomas, cyclin-D1 can be repressed by administering doxicycline-containing water to mice. We show that individual blockade of cyclin-D1 or BCL2 had moderate effects on cell survival, but the simultaneous inhibition of both proteins induced prominent cell proliferative arrest and apoptosis in human and mouse lymphomas. This therapeutic synergy was further enhanced by MCL1 depletion. Mechanistically, cyclin-D1 silencing released the pro-apoptotic final effector BAX, thus sensitizing cells to BCL2-mediated apoptosis. Finally, we show that the dual cyclin-D1 and MCL1 inhibitor roscovitine, combined with the BH3 mimetic ABT-737, was an effective therapy for primary MCL samples. These findings illustrate the potential benefit of combining therapies modulating cell-cycle and survival pathways aiming to cure patients with MCL.