134 | Chapter 5 the NF-kB signature patient groups were small, reflecting the heterogeneity within these groups. In addition, NF-kB activity negatively correlated with the expression of DNA replication genes, and patients with an NF-kB low signature had higher white blood cell counts, suggesting that these patients may suffer from a more aggressive disease. These results indicate that NF-kB could have tumor-suppressive qualities in B-ALL, as was suggested previously for other cell types.48 Importantly, several novel therapies for leukemias and lymphomas are aimed at the NF-kB and PI3K-AKT pathways and at CDK4.49-52 In light of our data, it is conceivable that such treatments might have adverse effects in leukemia patients by unleashing the oncogenic potential of RAG, thus driving (sub)clonal diversification and genomic instability of leukemic pre-B cells. Acknowledgements The authors thank Dr Craig Bassing (University of Pennsylvania School of Medicine, Philadelphia, PA) for providing wild-type and RAG2−/− mouse Abl pre-B cell lines; Drs Inês Trancoso and Jocelyne Demengeot (Instituto Gulbenkian, Oeiras, Portugal) for the RAG-reporter (green fluorescence protein) IRES-RFP construct; Dr Hergen Spits (Academic Medical Center, Amsterdam, The Netherlands) for the IkBaSR-IRES-YFP construct; Prof Dr Ellen van der Schoot and Dr Christa Homburg (Sanquin Research Institute, Amsterdam, The Netherlands) and Dr Edwin Sonneveld (Children’s Oncology Foundation [within the Stichting Kinderoncologie Nederland], The Hague, The Netherlands) for sharing patient material and data; and Dr Carol Schrader (University of Massachusetts Medical School, Worcester, MA) for helpful discussions. This work was supported by a fellowship from the Academic Medical Center and Innovational Research Incentives Scheme VIDI grant 016126355 from The Netherlands Organization for Scientific Research (both to J.E.J.G).
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