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

Autor: Ceccon M; Department of Health Science, University of Milano-Bicocca, Monza, Italy., Merlo MEB; Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.; Center for Experimental Research and Medical Studies (CERMS), Città della Salute e della Scienza, Torino, Italy., Mologni L; Department of Health Science, University of Milano-Bicocca, Monza, Italy., Poggio T; Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.; Center for Experimental Research and Medical Studies (CERMS), Città della Salute e della Scienza, Torino, Italy., Varesio LM; Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.; Center for Experimental Research and Medical Studies (CERMS), Città della Salute e della Scienza, Torino, Italy., Menotti M; Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.; Center for Experimental Research and Medical Studies (CERMS), Città della Salute e della Scienza, Torino, Italy., Bombelli S; Department of Health Science, University of Milano-Bicocca, Monza, Italy., Rigolio R; Surgery and Translational Medicine department, University of Milano-Bicocca, Monza, Italy., Manazza AD; Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.; Center for Experimental Research and Medical Studies (CERMS), Città della Salute e della Scienza, Torino, Italy., Di Giacomo F; Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.; Center for Experimental Research and Medical Studies (CERMS), Città della Salute e della Scienza, Torino, Italy., Ambrogio C; Molecular Oncology Program, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain., Giudici G; Tettamanti Research Centre, Pediatric Clinic, University of Milano-Bicocca, Monza, Italy., Casati C; MetaSystems s.l.r., Milano, Italy., Mastini C; Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.; Center for Experimental Research and Medical Studies (CERMS), Città della Salute e della Scienza, Torino, Italy., Compagno M; Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.; Center for Experimental Research and Medical Studies (CERMS), Città della Salute e della Scienza, Torino, Italy.; Department of Pathology, Children's Hospital and Harvard Medical School, Boston, USA., Turner SD; Division of Molecular Histopathology, Addenbrooke's Hospital Cambridge, Cambridge, UK., Gambacorti-Passerini C; Department of Health Science, University of Milano-Bicocca, Monza, Italy.; Section of Haematology, San Gerardo Hospital, Monza, Italy., Chiarle R; Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.; Center for Experimental Research and Medical Studies (CERMS), Città della Salute e della Scienza, Torino, Italy.; Department of Pathology, Children's Hospital and Harvard Medical School, Boston, USA., Voena C; Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.; Center for Experimental Research and Medical Studies (CERMS), Città della Salute e della Scienza, Torino, Italy.
Jazyk: angličtina
Zdroj: Oncogene [Oncogene] 2016 Jul 21; Vol. 35 (29), pp. 3854-3865. Date of Electronic Publication: 2015 Dec 14.
DOI: 10.1038/onc.2015.456
Abstrakt: 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.
Databáze: MEDLINE
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