Excess of NPM-ALK oncogenic signaling promotes cellular apoptosis and drug dependency

摘要: Most of the anaplastic large-cell lymphoma (ALCL) cases carry t(2;5; p23;q35) that produces fusion protein NPM-ALK (nucleophosmin-anaplastic kinase). NPM-ALK-deregulated kinase activity drives several pathways support malignant transformation cells. We found in ALK-rearranged ALCL cell lines, was distributed equal amounts between cytoplasm and nucleus. Only cytoplasmic portion catalytically active both lines primary ALCL, whereas nuclear inactive because heterodimerization with NPM1. Thus, about 50% is not sequestered as NPM-ALK/NPM1 heterodimers Overexpression or relocalization to by NPM genetic knockout knockdown caused ERK1/2 (extracellular signal-regulated kinases 1 2) increased phosphorylation death through engagement an ATM/Chk2- γH2AX (phosphorylated H2A histone family member X)-mediated DNA-damage response. Remarkably, human NPM-ALK-amplified resistant ALK tyrosine inhibitors (TKIs) underwent apoptosis upon drug withdrawal a consequence hyperactivation. Altogether, these findings indicate excess activation signaling induces via oncogenic stress responses. A 'drug holiday' where TKI treatment suspended could represent therapeutic option cells become amplification.