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Blood, 11 June 2009, Vol. 113, No. 24, pp. 6172-6181.
Prepublished online as a Blood First Edition Paper on February 26, 2009; DOI 10.1182/blood-2008-02-136762.
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Submitted February 20, 2008
Accepted January 30, 2009
Targeting the Notch1 and mTOR pathways in a mouse T-ALL model
Kathleen Cullion, Kyle M. Draheim, Nicole Hermance, Jennifer Tammam, Vishva M. Sharma, Christopher Ware, George Nikov, Veena Krishnamoorthy, Pradip K. Majumder, and Michelle A. Kelliher*
Department of Cancer Biology and the Cancer Center, University of Massachusetts Medical School, Worcester, MA, United States
The Department of Oncology/Pharmacology, Merck Research Laboratories, Boston, MA, United States
* Corresponding author; email: michelle.kelliher{at}umassmed.edu.
Mutations in NOTCH1 are frequently detected in patients with T cell acute lymphoblastic leukemia (T-ALL) and in mouse T-ALL models. Treatment of mouse or human T-ALL cell lines in vitro with  -secretase inhibitors (GSIs) results in growth arrest and/or apoptosis. These studies suggest GSIs as potential therapeutic agents in the treatment of T-ALL. To determine whether GSIs have anti-leukemic activity in vivo, we treated near end stage Tal1/Ink4a/Arf+/- leukemic mice with vehicle or with a GSI developed by Merck (MRK-003). We found that GSI treatment significantly extended the survival of leukemic mice, when compared to vehicle treated mice. Notch1 target gene expression was repressed and increased numbers of apoptotic cells were observed in the GSI treated mice, demonstrating that Notch1 inhibition in vivo induces apoptosis. T-ALL cell lines also exhibit PI3K/mTOR pathway activation, indicating that rapamycin may also have therapeutic benefit. When GSIs are administered in combination with rapamycin, mTOR kinase activity is ablated and apoptosis induced. Moreover, GSI and rapamycin treatment inhibits human T-ALL growth and extends survival in a mouse xenograft model. This work supports the idea of targeting NOTCH1 in T-ALL and suggests that inhibition of the mTOR and NOTCH1 pathways may have added efficacy.
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