Nucleophosmin–anaplastic lymphoma kinase associated with anaplastic large-cell lymphoma activates the phosphatidylinositol 3-kinase/Akt antiapoptotic signaling pathway

摘要: More than half of anaplastic large-cell lymphomas (ALCLs) have a chromosomal translocation t(2;5) that leads to the expression hybrid protein composed nucleolar phosphoprotein nucleophosmin (NPM) and lymphoma kinase (ALK) exhibits an unregulated tyrosine activity. We previously identified PLC-γ as crucial downstream signaling molecule NPM-ALK contributes its mitogenic potential. Here, we show recruits C-terminal SH2 domain phosphatidylinositol 3-kinase (PI 3kinase) p85 subunit. PI assays revealed is activated by in vivo, turn activating PKB/Akt NPM-ALK–expressing cells. The use 2 specific inhibitors, wortmannin LY294002, demonstrated requirement for growth NPM-ALK–transformed cell lines, well line established from patient with ALCL. Primary murine bone marrow retrovirally transduced showed transformed phenotype was reversible on treatment inhibitors. Flow cytometric analysis wortmannin-treated lines underwent apoptosis. Furthermore, apoptosis induced overexpression proapoptotic Bad could be partially blocked NPM-ALK. Thus, activates antiapoptotic 3-kinase/Akt pathway, which likely molecular pathogenesis