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Lymphoma

CUTLL1, a novel human T-cell lymphoma cell line with t(7;9) rearrangement, aberrant NOTCH1 activation and high sensitivity to γ-secretase inhibitors

Leukemia volume 20, pages 1279–1287 (2006)Cite this article

Abstract

Activating mutations in NOTCH1 are present in over 50% of human T-cell lymphoblastic leukemia (T-ALL) samples and inhibition of NOTCH1 signaling with γ-secretase inhibitors (GSI) has emerged as a potential therapeutic strategy for the treatment of this disease. Here, we report a new human T-cell lymphoma line CUTLL1, which expresses high levels of activated NOTCH1 and is extremely sensitive to γ-secretase inhibitors treatment. CUTLL1 cells harbor a t(7;9)(q34;q34) translocation which induces the expression of a TCRB-NOTCH1 fusion transcript encoding a membrane-bound truncated form of the NOTCH1 receptor. GSI treatment of CUTLL1 cells blocked NOTCH1 processing and caused rapid clearance of activated intracellular NOTCH1. Loss of NOTCH1 activity induced a gene expression signature characterized by the downregulation of NOTCH1 target genes such as HES1 and NOTCH3. In contrast with most human T-ALL cell lines with activating mutations in NOTCH1, CUTLL1 cells showed a robust cellular phenotype upon GSI treatment characterized by G1 cell cycle arrest and increased apoptosis. These results show that the CUTLL1 cell line has a strong dependence on NOTCH1 signaling for proliferation and survival and supports that T-ALL patients whose tumors harbor t(7;9) should be included in clinical trials testing the therapeutic efficacy NOTCH1 inhibition with GSIs.

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Acknowledgements

We thank Vladan Miljkovic in the ICG Microarray Facility for assistance with microarray experiments, the Cytogenetics Core Laboratory and Dr Subhadra Nandula for help with karyotype and FISH analysis.

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Authors and Affiliations

  1. Institute for Cancer Genetics, Columbia University, New York, NY, USA

    T Palomero, K C Barnes, P J Real, M L Sulis, V V Murty & A A Ferrando

  2. Department of Pathology, Columbia University, New York, NY, USA

    T Palomero, V V Murty, A I Colovai & A A Ferrando

  3. Department of Pediatrics, Columbia University, New York, NY, USA

    J L Glade Bender, M L Sulis & A A Ferrando

  4. Molecular Oncology Laboratory, Hospital Central de Asturias, Oviedo, Spain

    M Balbin

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  1. T Palomero
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  2. K C Barnes
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Correspondence to A A Ferrando.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Palomero, T., Barnes, K., Real, P. et al. CUTLL1, a novel human T-cell lymphoma cell line with t(7;9) rearrangement, aberrant NOTCH1 activation and high sensitivity to γ-secretase inhibitors. Leukemia 20, 1279–1287 (2006). https://doi.org/10.1038/sj.leu.2404258

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