Increased Expression of Fatty Acid Synthetic Enzymes in Hodgkin and Reed-Sternberg Cells of Classical Hodgkin Lymphoma
AC Seegmiller, SJ Olson, P Kapur, D Rakheja, W Chen. Vanderbilt University Medical Center, Nashville, TN; University of Texas Southwestern Medical Center, Dallas, TX
Background: Many solid tumors have increased synthesis of fatty acids (FAs) due to overexpression of FA synthetic enzymes, including acetyl-CoA carboxylase (ACC), fatty acid synthase (FASN), ATP-citrate lyase (ACLY), and stearoyl-CoA desaturase (SCD). Expression of these enzymes often correlates with more aggressive behavior and their inhibition leads to apoptosis of some cancer cells. However, little is known about FA metabolism in hematolymphoid neoplasms. This study evaluated the expression of FA synthetic enzymes in classical Hodgkin lymphoma (CHL).
Design: Expression of FA metabolism genes in four CHL cell lines was compared to that of 24 normal B-cell samples using an Oncomine interface (Compendia Bioscience, Ann Arbor, MI) on previously published gene expression microarray data (Basso et al., 2005). FASN protein expression was evaluated on 71 lymph nodes with untreated CHL by immunohistochemistry (IHC) using an anti-FASN monoclonal antibody (FASgen, Baltimore, MD). Staining intensity was evaluated on a scale of 0 (negative) to 4 (most intense) and was correlated with clinical parameters.
Results: Analysis of microarray data for CHL cell lines versus normal B-cell samples showed significant increases in mRNA of ACC (p=0.002), FASN (p<0.001), ACLY (p<0.001), and SCD (p<0.001). These increases correlated with increased expression of SREBP1 (p=0.003), the primary transcriptional regulator of these genes. IHC studies found FASN expression with variable intensity (mean=1.9) in the Hodgkin and Reed-Sternberg cells (HRS) of 66/71 (93%) CHL cases. FASN was largely absent from the surrounding inflammatory cells except for weak staining of scattered immunoblasts and germinal center cells. Mean staining intensity was significantly higher in widely disseminated (stage IV) cases versus all others (2.6±0.3 vs. 1.7±0.1; p=0.03).
Conclusions: Most HRS cells overexpress multiple enzymes of fatty acid synthesis, both in cell lines and primary tumor cells. FASN expression is particularly high in stage IV CHL, suggesting that it may correlate with more aggressive disease. There is a corresponding increase in SREBP1 expression, implying that it may play a role in upregulation of these metabolic pathways. These findings suggest a possible role for FA synthesis in CHL pathogenesis and may provide a new target for CHL therapy.
Wednesday, March 24, 2010 9:30 AM
Poster Session V # 202, Wednesday Morning