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Retinoic Acid Inhibits the Proliferative Response Induced by CD40 Activation and Interleukin-4 in Mantle Cell Lymphoma

¹ Immunovirology and Biotherapy Unit and ² Division of Experimental Oncology 1, Department of Pre-clinical and Epidemiological Research; ³ Division of Pathology; and ⁴ Division of Medical Oncology A, Centro di Riferimento Oncologico, IRCCS-National Cancer Institute, Aviano, Italy; ⁵ Hematology Section, Department of Biomedical Sciences and Advanced Therapies, University of Ferrara; ⁶ Division of Hematology, San Bortolo Hospital, Vicenza, Italy; ⁷ Division of Medical Oncology, General Hospital, Rovigo, Italy; and ⁸ Division of Pathology, San Raffaele H Scientific Institute, Milan, Italy

Requests for reprints: Riccardo Dolcetti, Immunovirology and Biotherapy Unit, Department of Pre-clinical and Epidemiological Research, Centro di Riferimento Oncologico, IRCCS-National Cancer Institute, Via Pedemontana Occidentale 12, 33081, Aviano (PN), Italy. Phone: 39-434-659-660, ext. 435; Fax: 39-434-659-659; E-mail: rdolcetti{at}cro.it.

Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin's lymphoma with poor response to therapy and unfavorable prognosis. Here, we show that retinoic acid (RA) isomers significantly inhibit the proliferation of both primary MCL cultures (n = 7) and established cell lines (Granta 519 and SP-53) as shown by [³H]thymidine uptake and carboxyfluorescein diacetate succinimidyl ester labeling coupled with cyclin D1 staining. RA induces cell accumulation in G₀-G₁ together with a marked up-regulation of p27^Kip1 by inhibiting ubiquitination and proteasome-dependent degradation of the protein. The p21^Cip1 inhibitor was also up-regulated by RA in Granta 519 cells, whereas the expression of cyclin D1 is unaffected. Most of RA-induced p27^Kip1 was bound to cyclin D1/cyclin-dependent kinase 4 complexes, probably contributing to the decreased cyclin-dependent kinase 4 kinase activity and pRb hypophosphorylation observed in RA-treated cells. Experiments with receptor-selective ligands indicate that RA receptor cooperates with retinoid X receptors in mediating RA-dependent MCL cell growth inhibition. Notably, RA isomers, and particularly 9-cis-RA, also inhibited the growth-promoting effect induced in primary MCL cells by CD40 activation alone or in combination with interleukin-4. Immunohistochemical analysis showed that significant numbers of CD40L-expressing lymphoid cells are present in lymph node biopsies of MCL patients. These results therefore further strengthen the possibility that triggering of CD40 by infiltrating CD40L+ cells may continuously promote the growth of MCL cells in vivo. On these grounds, our findings that RA inhibits basal MCL proliferation as well as MCL growth-promoting effects exerted by microenvironmental factors make these compounds highly attractive in terms of potential clinical efficacy in this setting.

Key Words: mantle cell lymphoma • retinoic acid, RAR/RXR • CD40 • p27^Kip1

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