Selective gamma-secretase targeting for NOTCH induced T cell acute lymphoblastic leukemia

NOTCH1 heterodimerization (HD) domain mutations are found at high frequency in T cell acute lymphoblastic leukemia (T-ALL). These mutant NOTCH1 receptors are constitutively cleaved by the gamma-secretase (GS) complex, independent of ligand, resulting in continuous NOTCH signaling. The key role for NOTCH in T-ALL resulted in a search for molecules targeting NOTCH. Gammasecretase inhibitors (GSIs) inhibit the proteolytic activity of the GS complex, preventing the final cleavage step of NOTCH receptors and thereby inhibiting NOTCH signaling. These GSIs were shown to have high anti-leukemic potential but are of limited use in the clinic due to strong dose-limiting toxicities related to inhibition of physiological NOTCH signaling in the gut. Most studies consider GS activity as one enzyme, whereas four GS complexes exist and gene targeting studies already indicated differential substrate processing among the different complexes. Here, we want to determine which GS complexes are responsible for processing of oncogenic mutant NOTCH1 receptors in T-ALL and exploit this to find new treatment options for NOTCH1 induced T-ALL. Selective targeting of GS complexes responsible for mutant NOTCH1 receptor processing in T-ALL is expected to maintain high anti-leukemic activity while sparing physiological NOTCH receptors and thereby circumventing toxicity problems seen with pan-GSIs.