P38 MAPK expression and activation predicts failure of response to CHOP in patients with Diffuse Large B-Cell Lymphoma.

Gabriel G Vega,Melisa Martinez-Paniagua,Alejandro Avilés-Salas,J Ramón Chalapud,Mario I Vega,Rogelio Hernandez-Pando,Rosana Pelayo,Sara Huerta-Yepez,Benjamin Bonavida,Héctor Mayani,Otoniel Martinez-Maza

doi:10.1186/s12885-015-1778-8

Abstract

BackgroundThe p38 MAPK is constitutively activated in B-NHL cell lines and regulates chemoresistance. Accordingly, we hypothesized that activated p38 MAPK may be associated with the in vivo unresponsiveness to chemotherapy in B-NHL patients.MethodsTissue microarrays generated from eighty untreated patients with Diffused Large B Cell Lymphoma (DLBCL) were examined by immunohistochemistry for the expression of p38 and phospho p38 (p-p38) MAPK. In addition, both Bcl-2 and NF-κB expressions were determined. Kaplan Meier analysis was assessed.ResultsTumor tissues expressed p38 MAPK (82 %) and p-p38 MAPK (30 %). Both p38 and p-p38 MAPK expressions correlated with the high score performance status. A significant correlation was found between the expression p-p38 and poor response to CHOP. The five year median follow-up FFS was 81 % for p38− and 34 % for p38+ and for OS was 83 % for p38− and 47 % for p38+. The p-p38+ tissues expressed Bcl-2 and 90 % of p-p38− where Bcl-2−. The coexpression of p-p38 and Bcl-2 correlated with pool EFS and OS. There was no correlation between the expression of p-p38 and the expression of NF-κB.ConclusionThe findings revealed, for the first time, that a subset of patients with DLBCL and whose tumors expressed high p-p38 MAPK responded poorly to CHOP therapy and had poor EFS and OS. The expression of p38, p-p38, Bcl2 and the ABC subtype are significant risk factors both p38 and p-p38 expressions remain independent prognostic factors.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1778-8) contains supplementary material, which is available to authorized users.

Highlights

The p38 Mitogen-Activated Protein Kinase (MAPK) is constitutively activated in B cell No-Hodgkin Lymphoma (B-Non-Hodgkin Lymphoma (NHL)) cell lines and regulates chemoresistance
The present study demonstrates a significant correlation between the expression of p38 and p-p38 MAPK and the development of resistance to CHOP treatment in patients with Diffuse Large B-Cell Lymphoma (DLBCL)
Altogether, the present findings show that activated p-p38 was expressed in 30 % of DLBCL and such an expression was associated with the Activated B-cell (ABC) phenotype and poor survival

Summary

Introduction

The p38 MAPK is constitutively activated in B-NHL cell lines and regulates chemoresistance. We hypothesized that activated p38 MAPK may be associated with the in vivo unresponsiveness to chemotherapy in B-NHL patients. The IPI was developed prior to the rituximab (anti-CD20 mAb) era and has recently been the subject of modifications for a better prediction of the outcome [5]. Two biological distinct pathophysiologic entities of DLBCL -as determined by gene expression profile-, namely, the Germinal Center B-cell subtype (GCB) and the Activated B-cell (ABC) subtype, and unclassified subtypes, derived from different cells of origin [6]. Patients with GCB-DLBCL have a better survival span than those with ABC-DLBCL [7]. The use of rituximab has improved the overall survival rates [8], a survival advantage in patients with GCB-DLBCL persists

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