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Excess of NPM-ALK oncogenic signaling promotes cellular apoptosis and drug dependency
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Excess of NPM-ALK oncogenic signaling promotes cellular apoptosis and drug dependency
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Journal Article
Excess of NPM-ALK oncogenic signaling promotes cellular apoptosis and drug dependency
2016
Overview
Most of the anaplastic large-cell lymphoma (ALCL) cases carry the t(2;5; p23;q35) that produces the fusion protein NPM-ALK (nucleophosmin-anaplastic lymphoma kinase). NPM-ALK-deregulated kinase activity drives several pathways that support malignant transformation of lymphoma cells. We found that in ALK-rearranged ALCL cell lines, NPM-ALK was distributed in equal amounts between the cytoplasm and the nucleus. Only the cytoplasmic portion was catalytically active in both cell lines and primary ALCL, whereas the nuclear portion was inactive because of heterodimerization with NPM1. Thus, about 50% of the NPM-ALK is not active and sequestered as NPM-ALK/NPM1 heterodimers in the nucleus. Overexpression or relocalization of NPM-ALK to the cytoplasm by NPM genetic knockout or knockdown caused ERK1/2 (extracellular signal-regulated protein kinases 1 and 2) increased phosphorylation and cell death through the engagement of an ATM/Chk2- and γH2AX (phosphorylated H2A histone family member X)-mediated DNA-damage response. Remarkably, human NPM-ALK-amplified cell lines resistant to ALK tyrosine kinase inhibitors (TKIs) underwent apoptosis upon drug withdrawal as a consequence of ERK1/2 hyperactivation. Altogether, these findings indicate that an excess of NPM-ALK activation and signaling induces apoptosis via oncogenic stress responses. A ‘drug holiday’ where the ALK TKI treatment is suspended could represent a therapeutic option in cells that become resistant by
NPM-ALK
amplification.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 13/95
/ 96
/ 96/2
/ 96/31
/ Anaplastic large-cell lymphoma
/ Animals
/ Cell Survival - drug effects
/ Cells
/ Cellular signal transduction
/ Dose-Response Relationship, Drug
/ Extracellular signal-regulated kinase
/ Extracellular Signal-Regulated MAP Kinases - metabolism
/ Histones
/ Humans
/ Kinases
/ Lymphoma
/ Lymphoma, Large-Cell, Anaplastic - genetics
/ Lymphoma, Large-Cell, Anaplastic - metabolism
/ Lymphoma, Large-Cell, Anaplastic - pathology
/ Medicine
/ Oncogene Proteins, Fusion - genetics
/ Oncogene Proteins, Fusion - metabolism
/ Oncology
/ Protein Kinase Inhibitors - pharmacology
/ Protein-Tyrosine Kinases - genetics
/ Protein-Tyrosine Kinases - metabolism
