Nucleophosmin-anaplastic lymphoma kinase of anaplastic large-cell lymphoma recruits, activates, and uses pp60c-src to mediate its mitogenicity

Daniel Cussac, Catherine Greenland, Serge Roche, Renyuan Bai, Justus Duyster, Stephan W. Morris, Georges Delsol, Michèle Allouche, Bernard Payrastre

Research output: Contribution to journalArticle

Abstract

Anaplastic large-cell lymphomas (ALCLs) are lymphomas of T or null phenotype often associated with a chromosomal translocation, t(2;5)(p23;q35). This translocation leads to the expression of a hybrid protein consisting of the N-terminal portion of nucleophosmin (NPM) and the intracellular domain of the anaplastic lymphoma kinase (ALK). NPM-ALK possesses a constitutive tyrosine kinase activity responsible for its oncogenic property through activation of downstream effectors such as phospholipase Cγ (PLC-γ) and the type IA phosphoinositide 3-kinase. Here, we show that the Src-kinases, particularly pp60c-src, associate with and are activated by NPM-ALK expression in various cells, and in cell lines established from patients with ALCL. The kinase activity and the tyrosine 418 of NPM-ALK are required for its association with Src-kinases. Y418F mutation of NPM-ALK impaired its association with Src-kinases and strongly reduced the proliferation rate of Ba/F3 cells. In agreement, Src-kinase inhibitors or pp60c-src siRNA significantly decreased the proliferation rate of NPM-ALK-positive ALCL cell lines. Moreover, using active or inactive forms of pp60c-src and NPM-ALK, we provide evidence that NPM-ALK is a potential substrate of pp60 c-src. Overall, our data place Src-kinases as new important downstream effectors of NPM-ALK and as attractive potential therapeutic targets for new ALCL treatment.

Original languageEnglish (US)
Pages (from-to)1464-1471
Number of pages8
JournalBlood
Volume103
Issue number4
DOIs
StatePublished - Feb 15 2004
Externally publishedYes

Fingerprint

Anaplastic Large-Cell Lymphoma
src-Family Kinases
Protein-Tyrosine Kinases
Phosphotransferases
Proto-Oncogene Proteins pp60(c-src)
Cells
Association reactions
nucleophosmin
anaplastic lymphoma kinase
Cell Line
Genetic Translocation
1-Phosphatidylinositol 4-Kinase
Type C Phospholipases
Phosphatidylinositols
Small Interfering RNA
Tyrosine
Lymphoma
Chemical activation
Phenotype
Mutation

ASJC Scopus subject areas

  • Hematology

Cite this

Nucleophosmin-anaplastic lymphoma kinase of anaplastic large-cell lymphoma recruits, activates, and uses pp60c-src to mediate its mitogenicity. / Cussac, Daniel; Greenland, Catherine; Roche, Serge; Bai, Renyuan; Duyster, Justus; Morris, Stephan W.; Delsol, Georges; Allouche, Michèle; Payrastre, Bernard.

In: Blood, Vol. 103, No. 4, 15.02.2004, p. 1464-1471.

Research output: Contribution to journalArticle

Cussac, D, Greenland, C, Roche, S, Bai, R, Duyster, J, Morris, SW, Delsol, G, Allouche, M & Payrastre, B 2004, 'Nucleophosmin-anaplastic lymphoma kinase of anaplastic large-cell lymphoma recruits, activates, and uses pp60c-src to mediate its mitogenicity', Blood, vol. 103, no. 4, pp. 1464-1471. https://doi.org/10.1182/blood-2003-04-1038
Cussac, Daniel ; Greenland, Catherine ; Roche, Serge ; Bai, Renyuan ; Duyster, Justus ; Morris, Stephan W. ; Delsol, Georges ; Allouche, Michèle ; Payrastre, Bernard. / Nucleophosmin-anaplastic lymphoma kinase of anaplastic large-cell lymphoma recruits, activates, and uses pp60c-src to mediate its mitogenicity. In: Blood. 2004 ; Vol. 103, No. 4. pp. 1464-1471.
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AU - Cussac, Daniel

AU - Greenland, Catherine

AU - Roche, Serge

AU - Bai, Renyuan

AU - Duyster, Justus

AU - Morris, Stephan W.

AU - Delsol, Georges

AU - Allouche, Michèle

AU - Payrastre, Bernard

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N2 - Anaplastic large-cell lymphomas (ALCLs) are lymphomas of T or null phenotype often associated with a chromosomal translocation, t(2;5)(p23;q35). This translocation leads to the expression of a hybrid protein consisting of the N-terminal portion of nucleophosmin (NPM) and the intracellular domain of the anaplastic lymphoma kinase (ALK). NPM-ALK possesses a constitutive tyrosine kinase activity responsible for its oncogenic property through activation of downstream effectors such as phospholipase Cγ (PLC-γ) and the type IA phosphoinositide 3-kinase. Here, we show that the Src-kinases, particularly pp60c-src, associate with and are activated by NPM-ALK expression in various cells, and in cell lines established from patients with ALCL. The kinase activity and the tyrosine 418 of NPM-ALK are required for its association with Src-kinases. Y418F mutation of NPM-ALK impaired its association with Src-kinases and strongly reduced the proliferation rate of Ba/F3 cells. In agreement, Src-kinase inhibitors or pp60c-src siRNA significantly decreased the proliferation rate of NPM-ALK-positive ALCL cell lines. Moreover, using active or inactive forms of pp60c-src and NPM-ALK, we provide evidence that NPM-ALK is a potential substrate of pp60 c-src. Overall, our data place Src-kinases as new important downstream effectors of NPM-ALK and as attractive potential therapeutic targets for new ALCL treatment.

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