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

Abstract

The chromosomal translocationt(11;14)(q13;q32) leading to cyclin-D1 overexpression plays an essential role in the development ofmantle cell lymphoma (MCL), an aggressive tumor that remains in-curable with current treatment strategies. Cyclin-D1 has been pos-tulated as an effective therapeutic target, but the evaluation of thistarget has been hampered by our incomplete understanding of itsoncogenic functions and by the lack of valid MCL murine models. Toaddress these issues, we generated a cyclin-D1–driven mouse modelin which cyclin-D1 expression can be regulated externally. Thesemice developed cyclin-D1–expressing lymphomas capable of recapit-ulating features of human MCL. We found that cyclin-D1 inactiva-tion was not sufficient to induce lymphoma regression in vivo;however, using a combination of in vitro and in vivo assays, weidentified a novel prosurvival cyclin-D1 function in MCL cells. Specif-ically, we found that cyclin-D1, besides increasing cell proliferationthrough deregulation of the cell cycle at the G1–S transition, seques-trates the proapoptotic protein BAX in the cytoplasm, thereby fa-voring BCL2’s antiapoptotic function. Accordingly, cyclin-D1 inhi-bition sensitized the lymphoma cells to apoptosis through BAXrelease. Thus, genetic or pharmacologic targeting of cyclin-D1 com-bined with a proapoptotic BH3 mimetic synergistically killed thecyclin-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 poten-tial benefit of simultaneously targeting cyclin-D1 and survival path-ways in patients with MCL. This effective combination therapy alsomight be exploited in other cyclin-D1–expressing tumors.