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Functional validation of the anaplastic lymphoma kinase signature identifies CEBPB and Bcl2A1 as critical target genes
Roberto Piva, … , Antonino Neri, Giorgio Inghirami
Roberto Piva, … , Antonino Neri, Giorgio Inghirami
Published December 1, 2006
Citation Information: J Clin Invest. 2006;116(12):3171-3182. https://doi.org/10.1172/JCI29401.
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Categories: Research Article Oncology

Functional validation of the anaplastic lymphoma kinase signature identifies CEBPB and Bcl2A1 as critical target genes

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Abstract

Anaplastic large cell lymphomas (ALCLs) represent a subset of lymphomas in which the anaplastic lymphoma kinase (ALK) gene is frequently fused to the nucleophosmin (NPM) gene. We previously demonstrated that the constitutive phosphorylation of ALK chimeric proteins is sufficient to induce cellular transformation in vitro and in vivo and that ALK activity is strictly required for the survival of ALK-positive ALCL cells. To elucidate the signaling pathways required for ALK-mediated transformation and tumor maintenance, we analyzed the transcriptomes of multiple ALK-positive ALCL cell lines, abrogating their ALK-mediated signaling by inducible ALK RNA interference (RNAi) or with potent and cell-permeable ALK inhibitors. Transcripts derived from the gene expression profiling (GEP) analysis uncovered a reproducible signature, which included a novel group of ALK-regulated genes. Functional RNAi screening on a set of these ALK transcriptional targets revealed that the transcription factor C/EBPβ and the antiapoptotic protein BCL2A1 are absolutely necessary to induce cell transformation and/or to sustain the growth and survival of ALK-positive ALCL cells. Thus, we proved that an experimentally controlled and functionally validated GEP analysis represents a powerful tool to identify novel pathogenetic networks and validate biologically suitable target genes for therapeutic interventions.

Authors

Roberto Piva, Elisa Pellegrino, Michela Mattioli, Luca Agnelli, Luigia Lombardi, Francesco Boccalatte, Giulia Costa, Bruce A. Ruggeri, Mangeng Cheng, Roberto Chiarle, Giorgio Palestro, Antonino Neri, Giorgio Inghirami

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Figure 2

NPM-ALK gene expression signature in ALCL cells derived by inducible shRNA.

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NPM-ALK gene expression signature in ALCL cells derived by inducible shR...
(A) GEP differentiates ALCL cells based on ALK expression. Unsupervised analysis of TS-TTA-A5, TS-TTA-A5M, and Su-DHL1-TTA-A5 cells untreated or treated with DOX for the indicated times. In the matrix, each column represents a sample, and each row a gene. The 21 samples were grouped according to the expression levels of the 267 most variable genes, after removal of the signals whose expression levels did not vary across experimental conditions. The color scale bar represents relative gene expression changes, normalized by the standard deviation. (B) The supervised analysis identified a selected number of genes specifically modified in untreated versus treated TS-TTA-A5 cells. Cell samples were cultured with (n = 6) and without (n = 6) DOX for the indicated times. The expression pattern of the identified genes in TS-TTA-A5M cells treated with DOX (84 hours) is shown on the right side. DEG, differentially expressed genes. (C) Functional stratification of ALK-regulated genes. Genes differentially expressed in TS-TTA-A5 treated with DOX were grouped according to their functional categories.
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