Activation of the NF-kappaB signalling pathway in diffuse large B-cell lymphoma: clinical implications.

ABSTRACT

AIM: To characterize the activation of the nuclear factor (NF)-kappaB pathway in diffuse large B-cell lymphoma (DLBCL) by immunohistochemistry. METHODS AND RESULTS: Sixty-six DLBCLs treated with anthracycline-containing chemotherapy were evaluated with antibodies against phosphorylated p65 (P-p65), p65, p50, p52, IKK alpha, and phosphorylated I kappaB (P-I kappaB). NF-kappaB activation was based on the expression of P-p65, P-I kappaB, and nuclear expression of p65 or p52 in the tumour cells. P-p65 and P-I kappaB were expressed in 13 (20%) and 17 cases (26%), respectively. p65, p52 and IKK alpha were found in the cytoplasm. A correlation was found between expression of P-p65 and P-I kappaB (P < 0.0001), but not between the two subtypes of DLBCL [germinal centre B cell and non-germinal centre (GC)]. P-p65+ tumours showed a better response to chemotherapy (P = 0.025) and a trend to increased event-free survival (P = 0.08). However, P-I kappaB expression was not associated with either clinical response or survival. Bcl-2 was not preferentially expressed on DLBCL tumours with NF-kappaB activation, as determined by expression of P-p65 and P-I kappaB proteins. CONCLUSIONS: NF-kappaB activation in DLBCL is preferentially mediated through the classical pathway and a novel mechanism involving phosphorylation of p65. Activation of NF-kappaB by P-p65 is associated with good prognosis. NF-kappaB activation is not confined to non-GC DLBCL exclusively.