Clinical significance of nuclear factor κB and chemokine receptor CXCR4 expression in patients with diffuse large B-cell lymphoma who received rituximab-based therapy

Abstract

Background/AimsThis study investigated the expression of nuclear factor κB (NF-κB) and the chemokine receptor (CXCR4) in patients with diffuse large B-cell lymphoma (DLBCL) who received rituximab-based therapy.MethodsSeventy patients with DLBCL and treated with rituximab-CHOP (R-CHOP) were included, and immunohistochemistry was performed to determine the expression of NF-κB (IκB kinase α, p50, and p100/p52) and CXCR4. To classify DLBCL cases as germinal center B-cell-like (GCB) and non-GCB, additional immunohistochemical expression of CD10, bcl-6, or MUM1 was used in this study. The expression was divided into two groups according to the intensity score (negative, 0 or 1+; positive, 2+ or 3+).ResultsThe median age of the patients was 66 years (range, 17 to 87), and 58.6% were male. Twenty-seven patients (38.6%) had stage III or IV disease at diagnosis. Twenty-three patients (32.9%) were categorized as high or high-intermediate risk according to their International Prognostic Indexs (IPIs). The overall incidence of bone marrow involvement was 5.7%. Rates of positive NF-κB and CXCR4 expression were 84.2% and 88.6%, respectively. High NF-κB expression was associated with CXCR4 expression (p = 0.002), and 56 patients (80.0%) showed coexpression. However, the expression of NF-κB or CXCR4 was not associated with overall survival and EFS. On multivariate analysis that included age, gender, performance status, stage, and the IPI, no significant association between the grade of NF-κB or CXCR4 expression and survival was observed.ConclusionsThe current study suggests that the tissue expression of NF-κB and CXCR4 may not be an independent prognostic marker in DLBCL patients treated with R-CHOP.

Evaluation of NF-κB subunit expression and signaling pathway activation demonstrates that p52 expression confers better outcome in germinal center B-cell-like diffuse large B-cell lymphoma in association with CD30 and BCL2 functions

“…Moreover, most previous studies have evaluated only a subset of the NF-κB subunits. [8][9][10][11][12][13][14][15] There are only two studies using all five subunits in DLBCL-a cohort of 88 patients with DLBCL by Odqvist et al 16 and a cohort of 45 patients with testicular DLBCL by Menter et al 17 In the current study, we evaluated expression of all five subunits of the NF-κB protein by immunohistochemistry and its clinical implications in a large cohort of patients with de novo DLBCL.…”

CXCR4 mutations in lymphoplasmacytic lymphoma lead to altered CXCR4 expression

“…In this study, although both CXCR4‐ mutated and non‐mutated cases showed CXCR4 expression, the 12 mutated cases showed higher expression of CXCR4, which was independent of the CXCR4 mutation type (Poulain et al , ). In addition, CXCR4 expression in other lymphomas has been studied by immunohistochemistry, but the localization of the protein was not described (Shin et al , ; Cai et al , ).…”

The role of G protein-coupled receptors in lymphoid malignancies

“…Increased CXCR4 expression was associated with worse survival in both ABC and GCB subtypes for 468 patients treated with the standard therapy R-CHOP [163] and a separate study of 94 patients found that those positive for CXCR4 has reduced survival and increased recurrence of disease [164]. However, a smaller cohort of 70 Korean patients did not identify an association between CXCR4 expression and survival [165]. At the cellular level, strong nuclear CXCR4 staining was correlated with systemic DLBCL whereas strong cytoplasmic CXCR5 staining was correlated with CNS involvement [166].…”

“…Furthermore, hypoxia was associated with upregulation of CXCR4 protein [167] and such an increase in CXCR4 expression is believed to increase cell dissemination [164]. IHC revealed that 80% of patients had CXCR4 coexpressed with NF-κB [165], which is often mutated in DLBCL, while CXCR4 itself contains an AIDCA somatic hypermutation hotspot that is suspect to mutation [168]. Various therapeutics targeting CXCR4 in DLBCL have been studied including the CXCR4 antagonist plerixafor which enhanced rituximab treatment [169], BTK140 which inhibited growth in cell lines [163], PIM inhibitors which impaired proliferation and CXCR4-mediated migration [170], and in vivo blocking of CXCR4 which was critical for regulatory T cell attraction to lymphoma [171].…”

“…Data were assembled from the following references: [2][3][4][10][14][68][72][76][102][106][135][151][163][164][165][172][173][175][178][189][190][191]. …”