Abstract

<div>Abstract<p><b>Purpose:</b> Clinical responses to the immmunomodulatory drug lenalidomide have been observed in patients with relapsed/refractory mantle cell lymphoma (MCL), although its mechanism of action remains partially unknown. We investigated whether the expression and subcellular localization of cyclin D1, a major cell-cycle regulator overexpressed in MCL, and the cyclin-dependent kinase inhibitor p27<sup>KIP1</sup>, could identify MCL cases sensitive to lenalidomide, and whether the compound could modulate cyclin D1/p27<sup>KIP1</sup> complexes in MCL cells.</p><p><b>Experimental Design:</b> MCL primary samples and cell lines were analyzed for subcellular levels of cyclin D1/p27<sup>KIP1</sup> complexes by Western blot, immunohistochemistry, immunoprecipitation, and flow cytometry. Activity of lenalidomide <i>in vitro</i> and its effect on cyclin D1/p27<sup>KIP1</sup> complexes were evaluated by real-time PCR, immunoprecipitation, immunofluorescence, and Western blot. <i>In vivo</i> validation was carried out in a mouse xenograft model of human MCL.</p><p><b>Results:</b> We found cyclin D1 and p27<sup>KIP1</sup> to be coordinately expressed in all the MCL samples tested. Immunoprecipitation analyses and siRNA assays suggested a direct role of cyclin D1 in the regulation of p27<sup>KIP1</sup> levels. The nuclear accumulation of both proteins correlated with MCL cell tumorigenicity <i>in vivo</i>, and sensitivity to lenalidomide activity <i>in vitro</i> and <i>in vivo</i>. Lenalidomide mechanism of action relied on cyclin D1 downregulation and disruption of cyclin D1/p27<sup>KIP1</sup> complexes, followed by cytosolic accumulation of p27<sup>KIP1</sup>, cell proliferation arrest, apoptosis, and angiogenesis inhibition.</p><p><b>Conclusions:</b> These results highlight a mechanism of action of lenalidomide in MCL cases with increased tumorigenicity <i>in vivo</i>, which is mediated by the dissociation of cyclin D1/p27<sup>KIP1</sup> complexes, and subsequent proliferation blockade and apoptosis induction. <i>Clin Cancer Res; 20(2); 393–403. ©2013 AACR</i>.</p></div>

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