Sự gia tăng phân hủy proteasome của ức chế kinase phụ thuộc cyclin p27 liên quan đến tỷ lệ sống sót tổng thể giảm ở lymphoma tế bào vỏ

Blood - Tập 95 - Trang 619-626 - 2000
Roberto Chiarle, Leo M. Budel, Jeffrey Skolnik, Glauco Frizzera, Marco Chilosi, Alessandra Corato, Gianni Pizzolo, Jory Magidson, Alessia Montagnoli, Michele Pagano, Brigitte Maes, Christine De Wolf-Peeters, Giorgio Inghirami

Tóm tắt

Lymphoma tế bào vỏ (MCL) là một khối u ác tính đặc trưng bởi sự biểu hiện không được điều hòa của cyclin D1 do t(11;14). Các cơ chế phân tử chịu trách nhiệm cho hành vi lâm sàng của MCL vẫn chưa rõ ràng. Các tác giả đã nghiên cứu sự biểu hiện của p53, E2F-1, và các ức chế CDK p27 và p21 trong 110 trường hợp MCL, liên quan sự biểu hiện của chúng đến hoạt động sinh sản (Ki-67). Để so sánh, họ cũng phân tích tương tự các lymphomas độ thấp (12 MALT, 16 CLL/SLL) và độ cao (19 DLCL). p53 được phát hiện thường xuyên hơn trong MCL tế bào lớn (l-MCL; 5 trên 7) so với MCL cổ điển (s-MCL; 13 trên 103) và DLCL (8 trên 19). Trong MCL và DLCL, tỷ lệ nhân E2F-1+ cao, tương quan với mức biểu hiện Ki-67 cao. Hầu hết các MCL (91 trên 112) và DLCL (12 trên 19) đều cho thấy sự mất p27; tuy nhiên, MALT và CLL/SLL lại dương tính với p27. Kỹ thuật phản ứng chuỗi polymerase phiên mã ngược và thử nghiệm phân hủy protein in vitro đã chứng minh rằng MCL có sự biểu hiện mRNA p27 bình thường nhưng hoạt động phân hủy protein p27 gia tăng thông qua con đường proteasome. Sự tương quan giữa biểu hiện p53 và p27 trong MCL với dữ liệu lâm sàng cho thấy một mối liên hệ giữa tỷ lệ sống sót tổng thể giảm và sự biểu hiện quá mức của p53 (P = 0,001), sự mất p27 (P = 0,002), hoặc cả hai. Mất p27 xác định bệnh nhân có kết quả lâm sàng kém hơn trong số các trường hợp âm tính với p53 (P = 0,002). Những phát hiện này cho thấy rằng MCL có sự biểu hiện protein chu kỳ tế bào khác biệt tương tự như lymphomas độ cao. Sự mất p27 và sự biểu hiện quá mức của p53 trong MCL là các dấu ấn dự đoán xác định bệnh nhân có nguy cơ cao. Việc chứng minh rằng mức p27 thấp trong MCL là do tăng cường phân hủy thông qua proteasome nên khuyến khích các thử nghiệm lâm sàng tiếp theo. (Blood. 2000;95:619-626)

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Tài liệu tham khảo

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