Abstract 5450: High expression of Krüppel-Like Factor 4 (KLF4) and its regulation by Yin Yang 1 (YY1) in non-Hodgkin's B-cell lymphomas: clinical implication.

Abstract

Abstract Non-Hodgkin Lymphoma (NHL) is a group of different kinds of cancer rising on the basis of monoclonal expansion of B and T Lymphocytes. Over 90% of NHL has its origin in B lymphocytes. The causes of NHL are poorly understood. Diffuse large B-cell lymphoma (DLBCL), the most common lymphoma in adults, and Burkitt s lymphoma are highly aggressive forms of NHL. It is of interest to characterize diverse transcription factors that are involved in the development of lymphoid progenitors because of their potential therapeutic applications. Krüppel-like factor 4 (KLF4) is a member of the KLF zinc-finger-containing transcription factor family. Evidence has established KLF4 as an oncogene or a tumor suppressor. Recent studies indicated the involvement of KLF4 in the regulation of apoptosis, proliferation, and differentiation of B cells and B-cell malignancies. By using a Tissue Micro Array (TMA), we have recently shown that NHLs have high expression of KLF4. The underlying mechanisms of the regulation of the expression of KLF4 in NHL are not yet understood. We have performed a bioinformatics analysis of the KLF4 promoter region and found that the transcription factor Yin Yang 1 (YY1) has putative binding sites on the KLF4 promoter, thus, hypothesizing the potential regulation of KLF4 by means of YY1 in NHL. This hypothesis was tested by various means: (1) In silico analyses by the CHIP (Chromatin Immunoprecipitation) experimental technique demonstrated that the KLF4 promoter contains four putative binding sites for YY1. We confirmed that the -126 site was a binding site for YY1 by CHIP analysis. (2) Using a reporter system with the KLF4 promoter, we have found that mutation of the putative binding site for YY1 (at -126) inhibited KLF4 expression and (3) Treatment of the Ramos cell line with siRNA for YY1 resulted in dowregulation of KLF4 expression. The clinical implication of YY1 in the transcriptional regulation of KLF4 was correlated by IHC in a TMA with 73 B-NHL samples and by western in B-NHL cell lines. The analyses showed that, in all of the tumor tissues, KLF4 expression had a positive correlation with YY1 expression and this correlation was markedly observed in the Burkitt subtype. Overall, our findings demonstrated that KLF4 can be transcriptionally regulated by YY1 in B-NHL. Previous findings demonstrated that YY1 regulates drug resistance in many cancers including B-NHL. Hence, the present findings suggest that both KLF4 and YY1 are prognostic biomarkers and therapeutic targets in NHL. Citation Format: Mario I. Vega, Alberto Valencia-Hipolito, Miriam Hernandez-Atenogenes, Gabriel G. Vega, Hector Mayani, Alfonso Mendez-Tenorio, Otoniel Martinez-Maza, Sara Huerta-Yepez, Benjamin Bonavida. High expression of Krüppel-Like Factor 4 (KLF4) and its regulation by Yin Yang 1 (YY1) in non-Hodgkin's B-cell lymphomas: clinical implication. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5450. doi:10.1158/1538-7445.AM2013-5450