Targeting pro-tumorigenic signaling pathways in hematolymphoid malignancies

Abstract

Hematolymphoid malignancies constitute diverse forms of cancers derived from hematopoietic and lymphoid tissues. Determining molecular alterations driving resistance to commonly used chemotherapies and defining disease mechanisms are of considerable relevance for understanding the pathogenesis of hematolymphoid malignancies. Here, using RNA-seq and proteomics analyses we identified several pro-tumorigenic signaling, including STAT3 and ERK pathways, to be involved in drug resistance in hematolymphoid malignancies. We demonstrated that the X-linked DDX3X is a crucial determinant in NHL aggressiveness. We established that STAT3 activation upregulates PD-L1 expression in cells of hematolymphoid malignancies. We optimized the “GapmeR” technology and developed a novel gene silencer “epAON” that were effective in knocking down STAT3 in cells of hematolymphoid malignancies and successful in inducing apoptosis in these cells. epAON molecules can be exploited for therapeutic applications. Overall, the data presented in this thesis greatly enhances the understanding of fundamental intracellular mechanisms involved in hematolymphoid malignancies.