T-Cell Receptor Signaling Proteins, BCL10 and Phosphorylated-P65 NFKB, Are Expressed in Peripheral T-Cell Lymphomas and Associated with Clinical Outcome

Background: Peripheral T-cell lymphomas (PTCL) are characterized by T-cell receptor (TCR) signaling alterations and NF-kB activation. Protein kinase C (PKC) is a family of proteins involved in signal transduction and mediates activation of the NF-kB pathway. In normal T cells, PKC 𝛉 plays a major role in TCR-mediated activation of a novel NF-kB pathway that involves phosphorylation of p65 at Serine 536 (P-p65^Ser536). BCL10 acts along the same pathway downstream of PKC 𝛉 to activate NF-kB. We thus investigated the relationship between PKC 𝛉, BCL10 and P-p65^Ser536 status in biopsy specimens from patients with PTCL.

Methods: Paraffin-embedded tissues obtained at diagnosis from 30 patients with nodal PTCL (PTCL unspecified, 21cases; angioimmunoblastic, 3; ALK⁻ anaplastic large-cell, 6) treated with curative intention were evaluated. Expression of PKC 𝛉, BCL10, and P-p65^Ser536 proteins were assessed using immunohistochemistry on a tissue microarray.

Results: Expression of PKC 𝛉 was detected in 22 of 30 cases (73%), BCL10 in 20 of 30 (67%), and P-p65^Ser536 in 21 of 30 (70%). Expression of BCL10 was associated with PKC 𝛉 (18 of 22) (P<0.0001), and P-p65^Ser536 (19 of 21) expression (P<0.0001). After a median follow-up of 60 months for surviving patients (range, 21–160 months), 5-year overall survival (OS) was 33%. Patients with BCL10 or P-p65^Ser536 positive tumors fared better, with a 5-year OS of 48% and 45%, respectively, versus 0% for those with negative tumors (P=0.029, and P=0.04, respectively). Remarkably, BCL10 expression identified a subgroup of patients within the low Ki-67 group (<80% positive tumor cells) with a different outcome; thus, within this subgroup patients with BCL10 positive tumors had a 5-year OS of 85% while it was 0% for those with BCL10 negative tumors (P=0.011). Multivariate analysis showed that BCL10, Ki-67, and P-p65^Ser536 expression were independent factors associated with OS (P=0.039, 0.029, and 0.050, respectively).

Conclusion: BCL10 is expressed in PTCL, correlates with PKC 𝛉 and P-p65^Ser536 NF-kB expression and it seems to be associated with improved survival in PTCL.