expression is in excess of eIF4G and 4EBP2 in VAL cells, this might PD1-PDL1 inhibitor 2 supplier explain why asTORi-triggered 4EBP2 recruitment does not affect eIF4G binding. Consistent with this model, eIF4E knockdown rendered VAL cells sensitive to asTORi effects on capdependent SC66 translation and cell death. In VAL cells with eIF4E knockdown, MLN0128 reduced MCL-1 expression and this might contribute to the increased apoptosis. In addition to conferring mTOR inhibitor resistance, a reduced 4EBP:eIF4E ratio might help to drive the tumor phenotype by facilitating translation of oncogenic mRNAs. eIF4E overexpression has been noted in many cancer types, and eIF4E overexpression in a mouse model cooperated with Myc to cause B cell transformation. In accord, a search of the Oncomine database revealed frequent overexpression of eIF4E mRNA in Burkitt��s Lymphoma, a cancer driven by Myc. The same gene array study showed that a majority of primary DLBCL specimens express higher levels of eIF4E mRNA compared to normal B cells or centroblasts. Notably, we were not able to achieve stable knockdown of eIF4E in some DLBCL cell lines. The cells infected with eIF4E shRNA viruses did not grow out of selection compared to the scrambled shRNA controls, supporting the idea that some DLBCLs depend on high levels of eIF4E for their survival. We searched the Basso Lymphoma dataset for patterns of 4EBP1 expression. One primary DLBCL specimen, out of 32 tested, had greatly reduced 4EBP1 mRNA expression relative to resting B lymphocytes and centroblasts. Therefore, 4EBP1 loss might occur in a fraction of primary human DLBCL tumors as observed in the VAL cell line. eIF4E expression in sample GSM44245 was higher than in normal B cells and similar to centroblasts. Nine other subtypes of B cell leukemia or lymphoma were analyzed in this dataset and none showed evidence for loss of 4EBP1 expression. Considering that there are three members of the 4EBP family, their tumor suppressor functions might be redundant. Of note, a very recent study showed that a large fraction of human pancreatic cancers lose expression of 4EBP1. However, 4EBP2 expression was not detected in pancreatic cancers or cell lines, a phenomenon that might facilitate tumor progression following 4EBP1 loss. In all B cell malignancies tested in the Basso Lymphoma microarray, 4EBP2 expression was similar
