NOTCH1: a therapeutic target for T cell acute lymphoblastic leukemia/lymphoma

T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) is an aggressive tumor that generally affects children but also arises in adults, affecting 1,500 people per year in the United States. T-ALL is often associated with hyperleucocytosis, large mediastinal masses and leptomeningeal infiltration at diagnosis. Activating mutations in NOTCH1 are present in about 50% of T-ALL cases and small molecule inhibitors of the g-secretase complex (GSIs), which effectively abrogate NOTCH1 signaling, have been proposed for the treatment of T-ALL. Despite this interest, the clinical development of GSIs has been hampered by our incomplete understanding of the effector pathways controlled by NOTCH1, the lack of clinical responses to GSI therapy and the development of gastrointestinal toxicity secondary to inhibition of NOTCH signaling in the gut. However, recent studies have elucidated important downstream mechanisms of NOTCH1-induced transformation and uncovered the molecular basis of sensitivity and resistance to GSI therapy. Moreover, combination therapies of GSIs with glucocorticoids have been shown to induce potent antileukemic effects in glucocorticoid resistant T-ALL and to ameliorate the gastrointestinal toxicity associated with systemic inhibition of NOTCH signaling. These recent developments may lead to novel rationally-designed and highly effective therapies targeting NOTCH1 signaling in T-ALL.