Abstract 4413: Mnk activity in diffuse large b-cell lymphoma: targeting translation

Augmentation of protein translation has been observed in a number of human malignancies. We have previously demonstrated that cap-dependent protein translation is dysregulated in diffuse large B-cell lymphoma (DLBCL). This cancer-associated phenomenon may result in the deregulation of many proto-oncogenes and tumor suppressors leading to multiple cellular abnormalities. A major rate-limiting step in cap-dependent translation is the binding of eIF4E to the 7-methyl guanosine cap in the 5′ untranslated region of mRNA thus, bridging the eIF4F pre-initiation complex with the ribosome and initiating translation. eIF4E has been widely implicated as a proto-oncogene contributing to cancer development in numerous published reports. In addition to the mTOR signaling network, there is a potential for eIF4E to be modulated by the mitogen-activated protein kinases via map kinase interacting kinases (MNK). MNK proteins (MNK1 or MNK2) exert their effect on eIF4E through phosphorylation of eIF4E at serine 209. This phosphorylation is believed to promote B-cell lymphomagenesis. However, the physiologically relevant regulatory mechanisms and potential for targeting eIF4E phosphorylation in human B-cell lymphoma is largely unexplored. This study aims to elucidate the mechanistic and therapeutic effects of MNK regulation of eIF4E phosphorylation in DLBCL. Counter-intuitively, we have found differential expression of MNK2 over MNK1 in activated B-cell (ABC) lymphoma versus germinal center B-cell (GCB) lymphoma subtypes even though both are known to converge to phosphorylate eIF4E. Interestingly, ERK does not play a significant role in activating MNK1/2 or affect the downstream phosphorylation of eIF4E in DLBCL, however, p38 plays an important role in eFI4E phosphorylation via MNK1. We show that phosphorylation of eIF4E by MNK is critical for malignant cell survival in both ABC and GCB DLBCL. The inhibition of p38 resulted in a significant and selective killing of DLBCL via inactivation of MNK1 and down-regulation of MCL1. Therefore, p38 inhibition may be a useful targeted approach in DLBCL through its suppression of MNK mediated eIF4E phosphorylation. Citation Format: Ari Landon, Parameswary A. Muniandy, Ronald B. Gartenhaus. Mnk activity in diffuse large b-cell lymphoma: targeting translation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4413. doi:10.1158/1538-7445.AM2014-4413