Regulation of p27 by S-Phase Kinase- Associated Protein 2 Is Associated with Aggressiveness in Diffuse Large B Cell Lymphoma (DLBCL)

Abstract The F-box protein S-phase kinase-associated protein 2 (Skp2) is one of the positive regulators of the cell cycle that promote ubiquitin-mediated proteolysis of the cyclin-dependent kinase inhibitor p27. In this study, we investigated the significance of Skp2 and p27 expression in diffuse large B cell lymphoma (DLBCL) treated with CHOP or CHOP-R. All patients (671) were diagnosed as having DLBCL at the twenty different hospitals and were treated with either CHOP (425) or CHOP-R (246) from 1996 to 2005. All specimens were histopathologically recomfirmed by one pathologist with expertise before entering into this study. Their clinical characteristics, including either the IPI or R-IPI factors, were evenly matched in both treatment groups. The median follow-up of living patients was 3.7 and 2.1 y for CHOP vs CHOP-R, respectively. Survival analyses were performed using the Kaplan-Meier method and the Cox regression model. There were 257 patients with high Skp2 expression (cutoff value >40% positive cells) (257/671,39.0%). High Skp2 expression was found in all IPI groups. Expression of p27 (P<.001) was associated with better overall survival (OS), whereas expression of Skp2 was associated with worse OS in CHOP treatment groups (P<.001). We also examined the prognostic impact of Skp2 according to various expression degree of Skp2, Skp2 expression remained a significant predictor of survival (<40%,40–79%,≥80%, P<.001). The multivariant analysis revealed that both the IPI score and the expression of Skp2 and p27 were independent predictors of OS and PFS in both treatment groups (P<.001). The patients with high Skp2 expression in combination with low p27 expression were related to worst survival in CHOP group (Fig1A). Interestingly, even in CHOP-R group, both high Skp2 expression and low p27 expression were the strong biomarker of worse prognosis (Fig 1B). DLBCL patients with high Skp2 expression did not benefit from the addition of R to CHOP. Conclusion: Addition of rituximab did not provide a beneficial outcome to DLBCL with high Skp2 and low p27 expression. Therapeutic strategies other than CHOP-R will be needed for DLBCL patients exhibiting a high Skp2 and low p27 expression at the time of diagnosis. Figure Figure

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LMO2 Protein Expression Predicts Survival in Patients with Diffuse Large B-Cell Lymphoma in the Pre- and Post-Rituximab Treatment Eras.

Blood ◽

10.1182/blood.v110.11.52.52 ◽

2007 ◽

Vol 110 (11) ◽

pp. 52-52 ◽

Cited By ~ 2

Author(s):

Yasodha Natkunam ◽

Pedro Farinha ◽

Eric D. Hsi ◽

Christine P. Hans ◽

Robert Tibshirani ◽

...

Keyword(s):

Protein Expression ◽

B Cell ◽

Cox Regression ◽

De Novo ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Prognostic Impact ◽

Independent Manner ◽

Large B Cell Lymphoma ◽

Large B Cell

Abstract Finding new prognostic markers in diffuse large B-cell lymphoma (DLBCL) is of importance because the disease is heterogeneous and current therapies fail to cure many affected patients. Previously, we showed that the expression of LMO2 mRNA was the strongest single predictor of superior outcome in patients with DLBCL in a multivariate model based on the expression of six genes (Lossos et al, NEJM 2004). Subsequently, we generated an anti-LMO2 monoclonal antibody and showed that LMO2 protein is expressed in a subset of germinal center-derived B-cell lymphomas including DLBCL, and that its expression predicted a superior outcome in DLBCL patients who were treated with anthracycline-based regimens (Natkunam et al, Blood 2006 & 2007). We have now expanded this cohort to include DLBCL patients treated at five international medical centers and have also tested the prognostic impact of LMO2 in patients treated with the addition of rituximab to CHOP (R-CHOP), a regimen which was recently demonstrated to improve the outcome of DLBCL patients (Coiffier et al, NEJM 2002; Sehn et al, JCO 2005; Habermann et al, JCO 2006; Pfreundschuh et al, Lancet Oncol 2006). Immunohistochemistry for LMO2 was performed on tissue microarrays containing cores of diagnostic biopsy specimens from patients with de novo DLBCL treated with anthracycline-based chemotherapy (280 patients) or with R-CHOP (80 patients) who had been followed for clinical outcome. The results show that in the pre-rituximab group staining for LMO2 was strongly correlated with overall survival (OS) and progression-free survival (PFS) (p=0.0018 and p=0.00071, respectively). Similarly, in the post-rituximab group LMO2 protein expression was associated with a significantly longer OS (p=0.0048) and PFS (p=0.0087). In multivariate Cox regression analyses, the expression of the LMO2 protein was found to be independent of the clinical IPI and most strikingly, was more robust than the conventional IPI in predicting OS and PFS, particularly in the post-rituximab DLBCL group of patients (OS p = 0.03, PFS p = 0.01). The capacity of LMO2 protein to identify DLBCL patients with improved outcome in an IPI-independent manner indicates its potential role in risk stratification of this disease. We conclude that the prognostic value of LMO2 protein expression remains significant in the era of R-CHOP treatment and recommend its assessment in all newly diagnosed DLBCL patients to confirm these results and eventually to optimize patient management.

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