1. ¹Institute for Cancer Genetics, Columbia University, New York, NY, USA
2. ²Department of Pathology, Columbia University, New York, NY, USA
3. ³Department of Pediatrics, Columbia University, New York, NY, USA
4. ⁴Molecular Oncology Laboratory, Hospital Central de Asturias, Oviedo, Spain

Correspondence: Dr AA Ferrando, Department of Pathology, Institute for Cancer Genetics-Columbia University, Russ Berrie Pavilion, Rm. 318A, 1150 St Nicholas Avenue, New York, NY 10032, USA. E-mail: af2196@columbia.edu

Received 9 March 2006; Accepted 24 March 2006; Published online 11 May 2006.

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 -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 -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.