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Acute Leukemias

The impact of NOTCH1, FBW7 and PTEN mutations on prognosis and downstream signaling in pediatric T-cell acute lymphoblastic leukemia: a report from the Children's Oncology Group

Leukemia volume 23, pages 1417–1425 (2009)Cite this article

Abstract

We explored the impact of mutations in the NOTCH1, FBW7 and PTEN genes on prognosis and downstream signaling in a well-defined cohort of 47 patients with pediatric T-cell acute lymphoblastic leukemia (T-ALL). In T-ALL lymphoblasts, we identified high-frequency mutations in NOTCH1 (n=16), FBW7 (n=5) and PTEN (n=26). NOTCH1 mutations resulted in 1.3- to 3.3-fold increased transactivation of an HES1 reporter construct over wild-type NOTCH1; mutant FBW7 resulted in further augmentation of reporter gene activity. NOTCH1 and FBW7 mutations were accompanied by increased median transcripts for NOTCH1 target genes (HES1, DELTEX1 and cMYC). However, none of these mutations were associated with treatment outcome. Elevated HES1, DELTEX1 and cMYC transcripts were associated with significant increases in transcript levels of several chemotherapy relevant genes, including MDR1, ABCC5, reduced folate carrier, asparagine synthetase, thiopurine methyltransferase, BCL2 and dihydrofolate reductase. PTEN transcripts positively correlated with HES1 and cMYC transcript levels. Our results suggest that (1) multiple factors should be considered with attempting to identify molecular-based prognostic factors for pediatric T-ALL, and (2) depending on the NOTCH1 signaling status, modifications in the types or dosing of standard chemotherapy drugs for T-ALL, or combinations of agents capable of targeting NOTCH1, AKT and/or mTOR with standard chemotherapy agents may be warranted.

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Acknowledgements

This work was supported by grant CA76641 from the National Cancer Institute, National Institutes of Health, grants from St Baldrick's Foundation, Leukemia Research Life (Detroit) and from the Sehn Family Foundation, the Dale Meyer Memorial Endowment for Leukemia Research, and the Ring Screw Textron Chair in Pediatric Cancer Research. Ms Gedman was supported by NIH training grant T32-CA009531. Dr Taub is a Scholar in Clinical Research of the Leukemia and Lymphoma Society. We thank the Children's Oncology Group ALL Biology Subcommittee for providing the clinical specimens and clinical data that made this study possible. The experimental insight and advice of Dr Zhanjun Hou (Karmanos Cancer Institute) with the NOTCH1 and FBW7 mutagenesis is greatly appreciated. Finally, we thank Dr Spyros Artavanis-Tsakonas (Harvard University, Cambridge, MA, USA) for providing wild-type NOTCH1 in pcDNA3 and Dr Lucio Miele (Loyola University, Chicago, IL, USA) for the gift of ICN1 in pcDNA3.

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Author notes

  1. K LaFiura and C L Haska: These authors contributed equally to this study.

Authors and Affiliations

  1. Graduate Program in Cancer Biology, Wayne State University School of Medicine, Detroit, MI, USA

    A Larson Gedman, S Kugel Desmoulin & L H Matherly

  2. Developmental Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Detroit, MI, USA

    Q Chen, Y Ge, K LaFiura, C L Haska, C Cherian, J W Taub & L H Matherly

  3. Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA

    Y Ge & J W Taub

  4. Department of Epidemiology and Health Policy Research, Children's Oncology Group, University of Florida, Gainesville, FL, USA

    M Devidas & S B Linda

  5. Children's Hospital of Michigan, Detroit, MI, USA

    J W Taub

  6. Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI, USA

    L H Matherly

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Larson Gedman, A., Chen, Q., Kugel Desmoulin, S. et al. The impact of NOTCH1, FBW7 and PTEN mutations on prognosis and downstream signaling in pediatric T-cell acute lymphoblastic leukemia: a report from the Children's Oncology Group. Leukemia 23, 1417–1425 (2009). https://doi.org/10.1038/leu.2009.64

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