TNF-a, retinoid acid and STAT4 pathways are differentially regulated by the HDAC inhibitors, SAHA, TSA and Sirtinol in Waldenstrom's Macroglobulinemia

Abstract

e14582 Background: HDAC inhibitors (HDAC-I) have emerged as a promising class of therapeutics for the treatment of lymphoplasmacytic malignancies, particularly in combination strategies. The basic mechanisms by which these agents modulate malignant cell growth remain to be clarified. In recent studies, we showed that SAHA, TSA, and Sirtinol have significant preclinical activity in Waldenstrom's macroglobulinemia (WM). As part of our effort to identify potential molecular targets for these agents, we performed gene expression profiling (GEP) using WM cells treated with these agents. Methods: We implemented the Bootstrap re-sampling technique on five BCWM1 GEP datasets to characterize the range of gene expression observed. Individual BCWM1 cells were treated with SAHA, TSA and Sirtinol at their established IC50 dosages for 6 and 24 hours prior to gene expression profiling. The genes which changed by two-fold, and fell outside of the 90% range of expression after drug treatment were identified. Results: SAHA upregulated TNF-α and downstream proteins including HSP70, TNFSF9, SERPINB2, as well as STAT4- dependent genes. Sirtinol upregulated metalloproteinase (MMP) and phosphodiesterase (PDE) family members through retinoic acid signaling. We also observed that SAHA, TSA and Sirtinol differentially upregulate elements of the MAP kinase pathways, including signaling through Erk, JNK, and p38 MAPK, indicating a global stress response to HDAC inhibition. Conclusions: The above studies suggest that HDAC inhibitors differentially effect growth of WM cells through both global as well as pathway specific alterations in signaling. Importantly, this data provides a platform for studying the mechanistic role of HDACs in WM, and provide a framework for the use of HDAC-I as single and combination. No significant financial relationships to disclose.