Single-pass transmembrane protein Extracellular domain – EGF-like repeats – binds Transmembrane domain Intercellular domain

T-lymphoblasts reproducing rapidly without differentiation 15% of childhood and 25% of adult ALL cases Current 5-year relapse-free survival rate is 75% in children and 50% in adults Survival rates are poor in patients with resistant primary disease or who relapse

Mutations are most frequently found in exons encoding the N-terminal and C- terminal of the heterodimerization domain Most Notch1 HD mutations are substitutions, deletions, and insertions which compromise a domain shielding Notch1’s cleavage, leading to ligand- hypersensitivity or ligand-independent NOTCH1 activation

NOTCH1 is important for the commitment of stem cells to develop into functional T cells – particularly for the assembly of pre–T-cell– receptor complexes in immature thymocytes

Activating Notch1 mutations are present in over 60% of human T-ALLs In childhood T-ALL, Notch1 mutations have been found to be prognostic of: – favorable early treatment response – improved long-term prognosis

Small molecule γ-secretase inhibitors (GSIs) can effectively block NOTCH1 signaling in T-ALL, and could be exploited as a targeted therapy in this disease Anti-NOTCH1 inhibitory antibodies, small peptide inhibitors of NOTCH signaling and combination therapies with GSIs show promise

Small molecule γ-secretase inhibitors (GSIs) can effectively block NOTCH1 signaling in T-ALL, and could be exploited as a targeted therapy in this disease Anti-NOTCH1 inhibitory antibodies, small peptide inhibitors of NOTCH signaling and combination therapies with GSIs are also promising

NCBI. “NOTCH1 notch 1 [ Homo sapiens (human) ]”.. Gannie Tzoneva and Adolfo A. Ferrando. “Recent Advances on NOTCH Signaling in T-ALL” Current Topics in Microbiology and Immunology (2012) 360: 163–182. Raphael Kopan. “Notch Signaling”. Cold Spring Harb Perspect Biol Li Xuan Tan. “Acute T-Cell Lymphoblastic Leukemia (T-ALL) & NOTCH1”.. Arnold S Freedman and Jon C Aster. “Clinical manifestations, pathologic features, and diagnosis of precursor T cell acute lymphoblastic leukemia/lymphoma”. UpToDate April 27, pathologic-features-and-diagnosis-of-precursor-t-cell-acute- lymphoblastic-leukemia-lymphoma “Activating NOTCH1 mutations predict favorable early treatment response and long-term outcome in childhood precursor T-cell lymphoblastic leukemia.” Blood Aug 15, 2006: