Tumor necrosis factor receptor-associated factor 1 gene overexpression in B-cell chronic lymphocytic leukemia: analysis of NF-kappa B/Rel-regulated inhibitors of apoptosis.
B-cell chronic lymphocytic leukemia (B-CLL) is characterized by a resistance toward apoptosis-inducing agents. Nuclear factor-kappaB (NF-kappaB)/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-kappaB/Rel-dependent inhibitors of apoptosis have not been collectively studied in B-CLL. We examined expression of known NF-kappaB/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-kappaB/Rel activity in B-CLL nuclear extracts was shown to bind to TRAF1 promoter elements. However, IkappaB 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-kappaB/Rel-regulated inhibitors of apoptosis, our findings indicate an IKK-independent regulation of TRAF1 in B-CLL.
Munzert
Gerd
G
Abteilung Innere Medizin III and Abteilung Innere Medizin I, Universität Ulm, Ulm, Germany. gerd.munzert@bc.boehringer-ingelheim.com
Kirchner
Dieter
D
Stobbe
Heike
H
Bergmann
Lothar
L
Schmid
Roland M
RM
Döhner
Hartmut
H
Heimpel
Hermann
H
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D019898:Autocrine Communication; D016022:Case-Control Studies; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051550:I-kappa B Kinase; D051034:Inhibitor of Apoptosis Proteins; D019476:Insect Proteins / Q000235:genetics; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism* / Q000473:pathology; D008875:Middle Aged; D016328:NF-kappa B / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D020572:Oncogene Proteins v-rel / Q000235:genetics; D017346:Protein Serine-Threonine Kinases; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D047990:TNF Receptor-Associated Factor 1; D015854:Up-Regulation
D051034:Inhibitor of Apoptosis Proteins; D019476:Insect Proteins; D016328:NF-kappa B; D009363:Neoplasm Proteins; D020572:Oncogene Proteins v-rel; D011506:Proteins; D012333:RNA, Messenger; D047990:TNF Receptor-Associated Factor 1; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human