Notch1 and its oncogenic role in

T-ALL

Kyle SmithBiol 445

Spring 2013

Notch1 protein structure

Single-pass transmembrane protein

• Extracellular domain– EGF-like repeats– binds

• Transmembrane domain• Intercellular domain

Notch1 signaling pathway

T-cell acute lympoblastic

leukemia (T-ALL)

• 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

Hematopoietic origins of T-ALL

Oncogenic mutations of

Notch1 in T-ALL

a) wild typeb) translocation leading to truncationc) mutation leading to destabilization of repeat complex

responsible for maintaining resting configurationd) mutation preventing protection of extracellular cleavage

sitee) mutation displacing extracellular cleavage site outside

repeat complexf) mutation increasing separation of repeat complex from the

membraneg) mutation impairing the ability of the intracellular domain to

be degraded in the nucleus

Activating mutations!

• 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 target genes and T-ALL

• 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

155 children with precursor T-ALL classified according to the presence or absence of Notch1 mutations

A. Kaplan-Meier estimate of event-free survival at 4 years B. Cumulative incidence of relapse

Prognostic and therapeutic value

• 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) ]”. <http://www.ncbi.nlm.nih.gov/gene/4851>.

• 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 2012.

• Li Xuan Tan. “Acute T-Cell Lymphoblastic Leukemia (T-ALL) & NOTCH1”. <http://tangen677s12.weebly.com/domains.html>.

• Arnold S Freedman and Jon C Aster. “Clinical manifestations, pathologic features, and diagnosis of precursor T cell acute lymphoblastic leukemia/lymphoma”. UpToDate April 27, 2012. < http://www.uptodate.com/contents/clinical-manifestations-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, 2006:1151-1157

References