Molecular analysis of Cyclin D1 in the development of mantle cell lymphoma

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Mantle cell lymphoma (MCL) has been recently recognized as one of the intractable lymphomas, and overexpression of Cyclin D1 caused by t(11;14) is identified as specific feature in them. However, concrete function of cyclin D1 in the lymphoma has not been fully disclosed yet. To examine it, we initially planed to suppress the function of Cyclin D1 by introducing PTD(TAT)-fused ScFv against cyclin D l, which can be isolated from anti-cyclin D1 MoAb-producing hybridoma (5D4). Because the pilot study using TAT oligopeptide as PTD demonstrated quite low introduction efficiency to leukemia/lymphoma cells including MCL cell lines, we needed to develop more efficient system for peptide/protein-delivery to hematopoietic cells. We also reconsidered that introducing p16 INK4a functional peptide could be more preferable to using ScFv against cyclin D1 for inhibition of cyclin D1's function because it is a specific inhibitor of the Cdk4/Cyclin D1 complexes. To introduce the p16 functional peptide … More into neoplastic lymphoid cells, we focused on peptide transporter system and attemped to develop the transporter with higher efficiency than that of previous system. Consequently, we succeeded in generating the novel peptide transporter that has both the expanded peptide-docking domain and the cell-permeable domain which serves to enhance the transduction efficiency of a cargo peptide into leukemia/lymphoma cells. The novel transporter was revealed to enable to target the peptide into MCL cells 20-30 times greater than the previous peptide delivery systems, which could reduce the amount of a cargo peptide to 1/50-1/100 of that in the previous systems. Following this result, we applied this system using the p16 functional peptide to highly aggressive leukemia/lymphoma cell lines (MCL, Burkitt's lymphomas, NK/T-cell lymphomas, blastic change of CML) if the growth inhibition took place or not.The result showed that remarkable suppression was observed in all of these leukemia/lymphoma cells (maximum 〜85%). Moreover, the p16 peptide introduced by the novel transporter caused a dramatic growth retardation of in vivo Burkitt's tumors in mouse models, which meant the utility of this system to in vivo lymphomas. We finished summarizing the data and are now submitting the manuscript to the journal of medical science. Partially related data were published in Eur. J. Immunol. Vol.33, p1-11, 2003 by Kondo et al. Less