In vitro validation of {gamma}-secretase inhibitors alone or in combination with other anti-cancer drugs for the treatment of T-cell acute lymphoblastic leukemia

• Published in: Haematologica (Roma) 2008-04, Vol.93 (4), p.533-542
• Main Authors: De Keersmaecker, Kim, Lahortiga, Idoya, Mentens, Nicole, Folens, Cedric, Van Neste, Leander, Bekaert, Sofie, Vandenberghe, Peter, Odero, Maria D, Marynen, Peter, Cools, Jan
• Format: Article
• Language: English
• ISSN: 0390-6078; 1592-8721
• DOI: 10.3324/haematol.11894

1 Human Genome Laboratory, Department of Molecular and Developmental Genetics, VIB, Leuven, Belgium; 2 Human Genome Laboratory, Center for Human Genetics, K.U. Leuven, Leuven, Belgium; 3 Division of Oncology, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain; 4 Department of Molecular Biotechnology, Faculty for Bioscience Engineering, Ghent University, Belgium; 5 Department of Human Genetics, K.U. Leuven, Leuven, Belgium Correspondence: Jan Cools, Campus Gasthuisberg O&N1, Herestraat 49 (box 602), B-3000 Leuven, Belgium. E-mail: jan.cools{at}med.kuleuven.be Background: Activating NOTCH1 mutations are common in T-cell acute lymphoblastic leukemia. Inhibition of NOTCH1 signaling with -secretase inhibitors causes cell cycle block, but only after treatment for several days. We further documented the effects of -secretase inhibitor treatment on T-cell acute lymphoblastic leukemia cell lines and tested whether combining -secretase inhibitors with other anti-cancer drugs offers a therapeutic advantage. Design and Methods: The effect of -secretase inhibitor treatment and combinations of -secretase inhibitors with chemotherapy or glucocorticoids was assessed on T-cell acute lymphoblastic leukemia cell lines. We sequenced NOTCH1 in T-cell acute lymphoblastic leukemia cases with ABL1 fusions and tested combinations of -secretase inhibitors and the ABL1 inhibitor imatinib in a T-cell acute lymphoblastic leukemia cell line. Results: -secretase inhibitor treatment for 5–7 days reversibly inhibited cell proliferation, caused cell cycle block in sensitive T-cell acute lymphoblastic leukemia cell lines, and caused differentiation of some T-cell acute lymphoblastic leukemia cell lines. Treatment for 14 days or longer was required to induce significant apoptosis. The cytotoxic effects of the chemotherapeutic agent vincristine were not significantly enhanced by addition of -secretase inhibitors to T-cell acute lymphoblastic leukemia cell lines, but -secretase inhibitor treatment sensitized cells to the effect of dexamethasone. NOTCH1 mutations were identified in all T-cell acute lymphoblastic leukemia patients with ABL1 fusions and in a T-cell acute lymphoblastic leukemia cell line expressing NUP214-ABL1 . In this cell line, the anti-proliferative effect of imatinib was increased by pre-treatment with -secretase inhibitors. Conclusions: Short-term treatment of T-cell acute lymphoblastic leukemia cell lines with -secretase inhibitors had limite