T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) is characterized by 
aberrant activation of NOTCH1 in over 60% of T-ALL cases. The high prevalence of 
activating NOTCH1 mutations highlights the critical role of NOTCH signaling in 
the pathogenesis of this disease and has prompted the development of therapeutic 
approaches targeting the NOTCH signaling pathway. Small molecule gamma secretase 
inhibitors (GSIs) can effectively inhibit oncogenic NOTCH1 and are in clinical 
testing for the treatment of T-ALL. Treatment with GSIs and glucocorticoids are 
strongly synergistic and may overcome the gastrointestinal toxicity associated 
with systemic inhibition of the NOTCH pathway. In addition, emerging new 
anti-NOTCH1 therapies include selective inhibition of NOTCH1 with anti-NOTCH1 
antibodies and stapled peptides targeting the NOTCH transcriptional complex in 
the nucleus.