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Titolo:
Expression of the oncogenic NPM-ALK chimeric protein in human lymphoid T-cells inhibits drug-induced, but not Fas-induced apoptosis
Autore:
Greenland, C; Touriol, C; Chevillard, G; Morris, SW; Bai, RY; Duyster, J; Delsol, G; Allouche, M;
Indirizzi:
CHU Purpan, CNRS UPR2163, UPCM, F-31059 Toulouse 03, France CHU Purpan Toulouse France 03 UPR2163, UPCM, F-31059 Toulouse 03, France St Jude Childrens Hosp, Dept Pathol, Memphis, TN 38105 USA St Jude Childrens Hosp Memphis TN USA 38105 Pathol, Memphis, TN 38105 USA Tech Univ Munich, Dept Internal Med 3, Lab Leukemogenesis, D-8000 Munich, Germany Tech Univ Munich Munich Germany D-8000 mogenesis, D-8000 Munich, Germany
Titolo Testata:
ONCOGENE
fascicolo: 50, volume: 20, anno: 2001,
pagine: 7386 - 7397
SICI:
0950-9232(20011101)20:50<7386:EOTONC>2.0.ZU;2-1
Fonte:
ISI
Lingua:
ENG
Soggetto:
RECEPTOR TYROSINE KINASE; NON-HODGKINS-LYMPHOMA; GROWTH-FACTOR RECEPTOR-1; FACTOR-I RECEPTOR; ANAPLASTIC LYMPHOMA; BCR-ABL; CHROMOSOMAL TRANSLOCATION; LEUKEMIC-CELLS; PHOSPHATIDYLINOSITOL 3-KINASE; MALIGNANT HISTIOCYTOSIS;
Keywords:
anaplastic large cell lymphoma; ALK; tyrosine kinase; chemotherapy; apoptosis;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
74
Recensione:
Indirizzi per estratti:
Indirizzo: Allouche, M CHU Purpan, CNRS UPR2163, UPCM, Ave Grande Bretagne, F-31059 Toulouse 03, France CHU Purpan Ave Grande Bretagne Toulouse France 03 03, France
Citazione:
C. Greenland et al., "Expression of the oncogenic NPM-ALK chimeric protein in human lymphoid T-cells inhibits drug-induced, but not Fas-induced apoptosis", ONCOGENE, 20(50), 2001, pp. 7386-7397

Abstract

Anaplastic large cell lymphomas (ALCLs), are frequently associated with, the t(2;5)(p23;q35) translocation, leading to the expression of NPM-ALK, a fusion protein linking nucleophosmin and anaplastic lymphoma kinase, a receptor tyrosine kinase. In ALCLs, dimerization of NPM-ALK leads to constitutive autophosphorylation and activation of the kinase, necessary for NPM-ALK oncogenicity.. To investigate whether NPM-ALK, like other oncogenic tyrosinekinases, can, inhibit drug-induced apoptosis, we permanently transfected NPM-ALK into Jurkat T-cells. As, in ALCLs, NPM-ALK was expressed as, a constitutively kinase-active 80 kDa protein, and could be detected by immunocytochemistry in nucleoli, nuclei and cytoplasm. Doxorubicin-induced apoptosis (assessed by cell morphology and annexin V-FITC binding), was significantlyinhibited in two independent NPM-ALK-expressing clones (5.2 +/- 1.8 and 7.5 +/- 0.8%, apoptosis), compared to control vector-transduced cells (36 +/-6.7%). Similar results were observed with etoposide. In contrast, Fas-induced apoptosis, was not inhibited. Cytochrome c release into the cytosol wasdelayed in doxorubicin-, but not anti-Fas-treated transfectant cells, indicating that apoptosis inhibition occurred upstream of mitochondrial events. Using NPM-ALK mutants, we demonstrated that inhibition of drug-induced apoptosis: (1) requires functional kinase activity, (2) does not involve phospholipase C-gamma, essential for NPM-ALK-mediated mitogenicity and (3) appears to: be phosphoinositide 3-kinase independent, despite a strong Akt/PKB activation observed in wild type NPM-ALK-expressing cells. These results suggest that the NPM-ALK antiapoptotic and mitogenic pathways are distinct.

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Documento generato il 05/12/20 alle ore 20:17:37