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NPM-ALK expression levels identify two distinct signatures in Anaplastic Large Cell Lymphoma of Childhood

ABSTRACT: Anaplastic large-cell lymphoma (ALCL) makes up approximately 15% of paediatric non-Hodgkin's lymphomas of childhood. The vast majority of them is associated with the t(2;5)(p23;q35) translocation that results in the expression of a hybrid oncogenic tyrosine kinase, NPM-ALK. In order to investigate ALCL biological characteristics we used transcriptional profiling approach. Genome-wide gene expression profiling, performed on 23 paediatric ALCL and 12 reactive lymph nodes specimens, showed two novel ALCL subgroups based on their NPM-ALK expression levels (named (ALK low and ALK high). Gene set enrichment analysis revealed, in ALK low samples, a positive enrichment of genes involved in the Interleukin signaling pathway, whereas we found increased expression of genes related to cell cycle progression and division in ALK high tumour samples, such as Aurora Kinase A (AURKA) and B (AURKB). Growth inhibition was observed upon administration of AURKA and AURKB inhibitors Alisertib and Barasertib and it was associated with perturbation of the cell cycle and induction of apoptosis. In conclusion we identified two novel ALCL subgroups, which display unique biological characteristics suggesting sensitivity to distinct targeted therapies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE78513 | GEO | 2016/11/04

SECONDARY ACCESSION(S): PRJNA313190

REPOSITORIES: GEO

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Project description:Anaplastic Large Cell Lymphomas (ALCL) represent a subset of lymphomas in which the Anaplastic Lymphoma Kinase (ALK) gene is frequently fused to the 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/EBPb and the anti-apoptotic 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. Experiment Overall Design: This series of microarray experiments contains the gene expression profiles of Anaplastic Large Cell Lymphoma (ALCL) cell lines (TS [a subclone of Sup-M2] and Su-DHL1) engineered to express ALK-A5 shRNA under a doxycycline-inducible promoter or treated with cell permeable pyrrolocarbazole-derived ALK inhibitors. A mutated ALK-A5M shRNA was used as control. Briefly, cells were transduced with pLV-DsRed-tTRKRAB, expanded, and used for transduction with pLVTH-GFP-shRNA lentiviral particles. Cells were induced with doxycycline (1 microg/ml) for 12 hours, double GFP+ DsRed+ cells selected by fluorescence-activated cell sorting. Cells expressing GFP in the absence of the inducer were removed by a second flow cytometry sorting, and expanded. shRNA expression was induced by doxycycline treatment for 72 or 84 hours. Drug treatments (300 nM), were performed in TS cells with ALK inhibitors (A2 or A3), mock compound (A1), or control diluent for 6 hours. 5 micrograms of total RNA was processed and hybridized to the Affymetrix HG-U133A chip following the manufacturer's instructions.

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NPM-ALK expression levels identify two distinct signatures in Anaplastic Large Cell Lymphoma of Childhood

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