Abstract
Anaplastic large cell lymphomas (ALCLs) are caused by chromosomal translocations that juxtapose the anaplastic lymphoma kinase (ALK) proto-oncogene to a dimerization partner, resulting in constitutive expression of ALK and ALK tyrosine kinase activity. One substrate of activated ALK in human ALCLs is the transcription factor Stat3, and its phosphorylation is accurately recapitulated in a new nucleophosmin (NPM)-ALK transgenic mouse model of lymphomagenesis. Here we show by gene targeting that Stat3 is required for the transformation of mouse embryonic fibroblasts in vitro, for the development of B-cell lymphoma in transgenic mice and for the growth and survival of both human and mouse NPM-ALK–transformed B and T cells. Ablation of Stat3 expression by antisense oligonucleotides significantly (P < 0.0001) impaired the growth of human and mouse NPM-ALK tumors in vivo. Pharmacological ablation of Stat3 represents a new candidate approach for the treatment of human lymphoma.
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Acknowledgements
We thank D.R. Littman, I. Matsumura, R. Pestell and R. Jove for providing the transgenic, luciferase and Stat3β constructs and A. Loonstra and J. Jonkers for the Cre-ERT-EGFP construct. A special thanks to D.R. Littman and K. Rajewsky for providing the CD4-Cre and CD19-Cre transgenic mice, respectively. We are grateful to E. Skolnick for the critical reading of the manuscript and for discussions. We also thank J. Howes for the technical assistance. Supported by grants from the Multiple Myeloma Research Foundation (to G.I.) and US National Institutes of Health (to G.I. and D.E.L.).
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Jim Karras is an employee of ISIS Pharmaceuticals.
Supplementary information
Supplementary Fig. 1
Stat3 is constitutively activated in mouse and human NPM-ALK positive cells. (PDF 107 kb)
Supplementary Fig. 2
Percentages of infection of Stat3loxP/− and Stat3−/− cells using with wild-type NPM-ALK or K210RNPM-ALK retroviruses. (PDF 41 kb)
Supplementary Fig. 3
Human Stat3 ASO block cell proliferation and induce cell death of ALCL-positive cells in vitro. (PDF 161 kb)
Supplementary Fig. 4
Stat3 ASO inhibit tumor growth and increase overall survival of mice bearing Stat3 positive NPM-ALK T cell tumors. (PDF 76 kb)
Supplementary Fig. 5
Biological changes induced by subcutaneous subministration of ASO. (PDF 186 kb)
Supplementary Fig. 6
Stat3 ASO leads to the downmodulation of mRNA levels of Stat3 in xenograft tissue tumor samples. (PDF 46 kb)
Supplementary Fig. 7
Tumors treated with Stat3 ASO undergo cell death. (PDF 226 kb)
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Chiarle, R., Simmons, W., Cai, H. et al. Stat3 is required for ALK-mediated lymphomagenesis and provides a possible therapeutic target. Nat Med 11, 623–629 (2005). https://doi.org/10.1038/nm1249
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DOI: https://doi.org/10.1038/nm1249
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