Tumor necrosis factor receptor-associated factor 1 gene overexpression in B-cell chronic lymphocytic leukemia: analysis of NF-κB/Rel–regulated inhibitors of apoptosis

• Published in: Blood 2002-11, Vol.100 (10), p.3749-3756
• Main Authors: Munzert, Gerd, Kirchner, Dieter, Stobbe, Heike, Bergmann, Lothar, Schmid, Roland M., Döhner, Hartmut, Heimpel, Hermann
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Apoptosis; Autocrine Communication; Biological and medical sciences; Case-Control Studies; Gene Expression Regulation, Neoplastic; Hematologic and hematopoietic diseases; Humans; I-kappa B Kinase; Inhibitor of Apoptosis Proteins; Insect Proteins - genetics; Leukemia, Lymphocytic, Chronic, B-Cell - metabolism; Leukemia, Lymphocytic, Chronic, B-Cell - pathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Middle Aged; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; NF-kappa B - genetics; Oncogene Proteins v-rel - genetics; Protein-Serine-Threonine Kinases; Proteins - genetics; Proteins - metabolism; RNA, Messenger - analysis; RNA, Messenger - biosynthesis; TNF Receptor-Associated Factor 1; Up-Regulation
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V100.10.3749

B-cell chronic lymphocytic leukemia (B-CLL) is characterized by a resistance toward apoptosis-inducing agents. Nuclear factor-κB (NF-κB)/Rel has been shown to regulate the expression of antiapoptotic genes, such as members of the inhibitor of apoptosis protein (IAP) and tumor necrosis factor receptor-associated factor (TRAF) gene families. Expression and regulation of NF-κB/Rel–dependent inhibitors of apoptosis have not been collectively studied in B-CLL. We examined expression of known NF-κB/Rel–regulated antiapoptotic genes by RNAse protection assay, real-time polymerase chain reaction, and immunoblotting in patients with B-CLL. TRAF1 and to a lesser extent TRAF2 were overexpressed in B-CLL lymphocytes as compared with normal CD19+ B cells. TRAF1 overexpression did not correlate with markers of disease progression or overall survival. Furthermore, we found high constitutive expression of the IAP genes c-IAP-1, c-IAP-2, and XIAP both in normal and B-CLL lymphocytes. Focusing on the regulation of TRAF1, NF-κB/Rel activity in B-CLL nuclear extracts was shown to bind to TRAF1 promoter elements. However, IκB kinase (IKK) activity was not increased in CLL lymphocytes as compared with normal CD19+ B cells. The known IKK inhibitor sulfasalazine did not compromise TRAF1 expression. Thus, although our study revealed a common expression pattern of NF-κB/Rel–regulated inhibitors of apoptosis, our findings indicate an IKK-independent regulation of TRAF1 in B-CLL.