Cyclin-Dependent Kinase Subunit 1B (Cks1B) Constitutes an Independent Prognostic Marker in Diffuse Large B-Cell Lymphoma (DLBCL)
U Keller, S Haug, T Schuster, A Tzankov, S Dirnhofer, M Kremer. Technical University, Munich, Germany; University of Basel, Basel, Switzerland; Klinikum Muenchen, Munich, Germany
Background: P27Kip1 is a negative regulator of the cell cycle. The regulation of p27Kip1 protein levels is mediated by the E3 ubiquitin ligase SCFSkp2. The S-phase kinase-associated protein 2 (Skp2) and Cks1B confer substrate specificity towards p27Kip1. In contrast to other malignancies, the prognostic role of p27Kip1 and its regulators Cks1B and Skp2 in DLBCL remains unclear. We have previously shown that c-Myc mediates p27Kip1 suppression via induction of Cks1B in a murine Burkitt lymphoma model. AIMS: To study the prognostic utility of p27Kip1, Cks1B, and Skp2 in a large series of DLBCL, and to correlate the expression profiles with c-Myc alterations.
Design: Formalin-fixed and paraffin embedded biopsies of 221 patients with DLBCL were analyzed using immunohistochemistry for p27Kip1, Cks1B, Skp2, Ki67, c-Myc and FISH for c-Myc alterations. Stainings for CD10, CD30, MUM1, BCL2, and BCL6 were performed to group DLBCL in germinal center GC or non-GC subtypes. The results were correlated with clinical data by uni- and multivariate survival analyses.
Results: Of 221 patients, 115 were of the non-GC, whereas 106 showed a GC subtype. There was no statistically significant difference in the p27 Kip1, Cks1B, and Skp2 expression across the two subtypes. However, high Cks1B levels were associated with a significantly diminished event free survival (EFS), regardless of the subtype (20 vs.94 months, p=0.01) Additionally, a trend towards inferior overall survival in cases showing high Cks1B expression was observed. Both proteins correlated with the proliferation index (Ki67) (p=0.03). The mean proliferation index was 53% in the non-GC-, compared to 70% in the GC-group. FISH analysis showed 3 c-MYC breaks and 5 gains in the non-GC-, in contrast to 3 breaks and 12 gains in the GC-group. Protein levels of c-Myc and Cks1B correlated positively (p=0.001).
Conclusions: Our results suggest that the levels of Cks1B may serve as a independent prognostic marker in DLBCL. Cks1B expression correlates with c-Myc expression on protein level, and is associated with increased proliferation. Furthermore our data indicate a function of Cks1B independent from p27 Kip1 regulation.
Wednesday, March 24, 2010 9:30 AM
Poster Session V # 192, Wednesday Morning