Alterations of the p53, Rb and p27 Tumor Suppressor Pathways in Diffuse Large B-cell Lymphomas

• Published in: Anticancer research Vol. 27; no. 4B; pp. 2345 - 2352
• Main Authors: BAI, Maria, TSANOU, Elena, SKYRLAS, Angelos, SAINIS, Ioannis, AGNANTIS, Niki, KANAVAROS, Panagiotis
• Format: Journal Article
• Language: English
• Published: Attiki International Institute of Anticancer Research 01.07.2007
• Subjects: B-Lymphocytes - pathology; Biological and medical sciences; Cell Differentiation - physiology; Cyclin D2; Cyclin-Dependent Kinase Inhibitor p21 - biosynthesis; Cyclin-Dependent Kinase Inhibitor p27 - metabolism; Cyclins - biosynthesis; Hematologic and hematopoietic diseases; Humans; Immunohistochemistry; Immunophenotyping; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphoma, B-Cell - metabolism; Lymphoma, B-Cell - pathology; Lymphoma, Large B-Cell, Diffuse - metabolism; Lymphoma, Large B-Cell, Diffuse - pathology; Medical sciences; Proto-Oncogene Proteins c-mdm2 - biosynthesis; Retinoblastoma Protein - metabolism; Signal Transduction; Tumor Suppressor Protein p14ARF - biosynthesis; Tumor Suppressor Protein p53 - metabolism; Tumors; Rb protein; KIP1 Gene; Cancerology; TP53 Gene; Retinoblastoma gene; Lymphoproliferative syndrome; Cell cycle; B cell neoplasm; Diffuse large B cell lymphoma; Malignant hemopathy; Diffuse large B-cell lymphomas; Tumor suppressor gene
• ISSN: 0250-7005; 1791-7530

Diffuse large B-cell lymphomas (DLBCL) display defects in cell cycle and apoptosis regulation. Therefore, the immunohistochemical expression patterns of the proteins p14, p21, Hdm2 and cyclin D2 were analyzed in relation to the previously reported expression of other major cell cycle proteins (p53, Rb, p16, p27, Ki-67 and cyclins A, B1, D2, D3 and E), apoptosis-associated proteins (bcl2, bcl-xl, bax, bak, bad and bid) and the B-cell differentiation immunophenotypes. Expression of the proteins p14, p21, Hdm2 and cyclin D2 was observed in 62/71 (87%), 22/76 (29%), 35/74 (47%) and 11/77 (14%) cases, respectively. Immunohistochemical alterations of the p53 (p53-Hdm2-p21-p14), Rb (Rb-p16-cyclin D [D2 or D3]) and p27 (p27-cyclin E) pathways were found in 56/77 (73%), 53/79 (67%) and 54/79 (68%) cases, respectively. Concomitant alterations of the p53-Rb, p53-p27 and Rb-p27 pathways were found in 40/77 (52%), 38/77 (50%) and 36/79 (46%) cases, respectively. Three concomitant alterations of the p53-Rb-p27 pathways were found in 28/79 (35%) cases. The main findings of the present study were the following: alterations of the p27 pathway were associated with higher expression of Ki-67 (p=0.023); concomitant alterations of the p53-Rb pathways and the p53-p27 pathways were associated with higher expression of cyclin A (p=0.015 and p=0.021, respectively) and concomitant alterations of the p53, Rb and p27 pathways were associated with higher expression of cyclin A (p=0.013). Since cyclin A supports DNA replication, centrosome duplication and mitosis, these findings indicate that concomitant alterations of the p53, Rb and p27 pathways in DLBCL may have cooperative effects resulting in increased neoplastic cell proliferation. This might explain, at least partially, the association between concurrent aberrations of the p53, Rb and p27 pathways and aggressive clinical behavior in DLBCL.