Abstract 3550: Expression of Oct-2, OCA-B, BCL6, PU.1 and IRF8 predicts prognosis in Diffuse Large B Cell Lymphoma patients
Authors: Rojas Bilbao Erica A. , Bal de Kier Joffe Elisa D. , Zerga Marta E. , Puricelli Lydia I. , Ranuncolo Stella Maris N. 
Published: August 2015

Diffuse Large B Cell Lymphoma (DLBCL) is the most common B cell Non Hodgkin lymphoma in adults.  While 50% of patients are cured with standard therapy, a large fraction either relapse or have primary refractory disease. Relapse is the major cause of treatment failure and death in these patients.  Remains imperative the availability of markers that could predict response to therapy.

DLBCL is a heterogeneous group of diseases that arise from germinal center (GC) B cells. Gene expression profiling has classified DLBCL into two subgroups Activated B Cell Like (ABC) and Germinal Center B Cell Like (GCB). Multiple mutations associated with its biology have been identified by next generation sequencing but little is known about their prognostic role.

The transit of B cells through the GC is controlled by sequential activation and repression of transcription factors. BCL6 role in GC development and derived B cell lymphomas is well known. Oct2 and its cofactor OCAB control BCL6 expression being responsible for its up regulation in centroblasts (Blood 144; 22). Oct2/OCAB recognize a non canonical binding site in BCL6 promoter. Oct2 is recruited to its target gene by PU1/IRF8. Co-IPs assays in BJAB and HBL1 showed the interactions among these factors. The downregulation of PU1 or IRF8 expression using shRNAs significantly decreased Oct2/OCAB binding enrichment on BCL6 promoter. Based on these observations we decided to analyze the expression of the GC highly expressed Oct2, OCAB, BCL6, PU1 and IRF8 transcription factors by immunohistochemistry, in paraffin embedded biopsies of DLBCL patients obtained at diagnosis. We included 73 patients [38 male Md age and range 59.07 (25-85); 35 female 59.4 (17-82)]. The univariate analysis showed no correlation between the percentage of positive tumor cells and the clinical-pathological parameters indicative of prognosis. Similarly there was a lack of correlation both with the immune-phenotype markers routinely evaluated and the growth fraction marker Ki67. The Kaplan-Meier study showed that tumors with Oct2, BCL6 and IRF8 expression higher than 70% [(Log Rank Test X2 = 3,7) p = 0.05; 4,0 p = 0.04 and 4,0 p = 0.04 respectively] correlated with poor prognosis and reduced OS. This correlation remained independent of the tumor stage in the multivariate analysis. Meanwhile 88%, 54% and 60% of patients showed more than 70% of positive tumor cells for Oct2, BCL6 and IRF8, only 17.8% and 5.5% reached that percentage for OCAB and PU1. Furthermore, OCAB and PU1 expression was completely lost in 42.5% and 63% of the patients. The OCAB and PU1 expression loss correlated with poor prognosis and reduced OS. We believe that the evaluation of these molecules would be useful to assess prognosis in DLBCL patients at the time of diagnosis. All together these findings imply potential therapeutic considerations since we might need to attack simultaneously diverse interactions among multiple proteins in this B cell lymphoma.

Citation Format: Erica A. Rojas Bilbao, Elisa D. Bal de Kier Joffe, Marta E. Zerga, Lydia I. Puricelli, Stella Maris N. Ranuncolo. Expression of Oct-2, OCA-B, BCL6, PU.1 and IRF8 predicts prognosis in Diffuse Large B Cell Lymphoma patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3550. doi:10.1158/1538-7445.AM2015-3550