Unraveling the molecular landscape: a comparative analysis of PI3K and MAPK signaling pathways in plasmablastic lymphoma and diffuse large B-cell lymphoma with therapeutic implications

Plasmablastic lymphoma (PBL) is a rare and aggressive subtype of non-Hodgkin lymphoma that shares features with diffuse large B-cell lymphoma (DLBCL). While significant progress has been made in treating DLBCL, the prognosis for PBL remains poor, highlighting the need to identify new therapeutic targets. Using RNA expression analysis, we compared the expression of genes involved in the phosphatidylinositol-3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signaling pathways between PBL and DLBCL. We used critical PI3K (n = 201) and MAPK (n = 57) signaling probe sets to achieve this objective. Our results demonstrate unique molecular mechanisms underlying PBL pathogenesis compared to DLBCL, particularly within the PI3K and MAPK signaling pathways. We found that elevated STAT3 expression in PBL correlates with hyperactive MAPK and PI3K pathways, unlike DLBCL. Additionally, the hyperactivation of the PI3K signaling axis in PBL is unrelated to B-cell receptor or phosphatase and tensin homolog activity, indicating a distinct mechanism compared to DLBCL. Furthermore, we observed unique activation patterns in MAPK pathways between PBL and DLBCL, with PBL exhibiting high expression of the neurotrophic tyrosine kinase receptor (NTKR) family, specifically NTRK1 and NTRK2 genes, which have therapeutic potential. We also found that neither human immunodeficiency virus nor Epstein-Barr virus infection influences gene expression profiles linked to PI3K and MAPK signaling in PBL. These findings could lead to adapting targeted therapies developed for DLBCL to address the specific needs of PBL patients better and contribute to developing novel, targeted therapeutic strategies to improve patient outcomes.