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NOTCH WAS FIRST IDENTIFIED IN THE FRUIT FLY DROSOPHILA

NOTCH SIGNALING REGULATES MULTIPLE ASPECTS OF INVERTEBRATE AND VERTEBRATE

DEVELOPMENT.

WHAT HAPPENS TO A MOUSE THAT LACKS NOTCH 1?

NOTCH IS REQUIRED FOR T-CELL PROGENITORS OF THE AB LINEAGE TO

PROGRESS PAST THE DN3 B SELECTION CHECKPOINT FOR T-CELL DEVELOPMENT

NOTCH ENCODES A CELL SURFACE RECEPTORWITH A TRANSMEMBRANE-BOUND LIGAND

UPON LIGAND BINDING, NOTCH IS PROTEOLYTICALLY CLEAVED AND THE

CYTOPLASMIC FRAGMENTACTS AS A TRANSCRIPTION FACTOR

NOTCH1 GENE IN GENOMIC LOCATION

T- ACUTE LYMPHOBLASTIC LEUKEMIA IS AN AGGRESSIVE CANCER THAT TYPICALLY AFFECTS

CHILDREN AND ADOLESCENTS

Subtype Frequency

Early Pre-B cell 60%- 65%

Pre-B cell 20%- 25%

Mature B cell 2%- 3%

T cell 15%- 18%

CHROMOSOMAL TRANSLOCATION LEADING TO T-ALL

THE T(7;9)(Q34;Q34.3) TRANSLOCATION, WHICH OCCURS IN ~1% OF T-ALL, LEADS TO THE CONSTITUTIVE EXPRESSION OF

ACTIVE NOTCH1

NOTCH1 MUTATIONS HAVE BEEN REPORTED TO OCCUR IN 10 TO 15% OF

HEAD AND NECK SQUAMOUS CELL CARCINOMAS (HNSCC)

CURRENT TREATMENT OF T-ALL CONSISTS OF CHEMOTHERAPY TO

ACHIEVE REMISSION AND CENTRAL NERVOUS SYSTEM (CNS) PROPHYLAXIS TO PREVENT T-ALL FROM SPREADING TO

THE BRAIN OR SPINAL CORD

IDENTIFICATION OF GENETIC ABERRATIONS, SUCH AS NOTCH1, IS IMPORTANT IN AN ATTEMPT TO DESIGN NOVEL FORMS OF

TARGETED THERAPIES.

ACUTE LYMPHOBLASTIC LEUKEMIAS ARE RESPONSIBLE FOR ABOUT 1,400 DEATHS A YEAR IN THE U.S., AND IT CAN PROGRESS QUICKLY IF

UNTREATED. HOWEVER, ALL IS ONE OF THE MOST CURABLE CANCERS AND SURVIVAL RATES ARE

NOW AT AN ALL-TIME HIGH.• Today, more

than 95% of children with ALL attain remission.

• 60 - 80% of adults with ALL can expect to achieve full remission with standard treatments, and 35 - 40% survive beyond 2 years with aggressive treatments

A NOTABLE DIFFERENCE OF RELAPSE-FREE SURVIVAL EXISTS BETWEEN PATIENTS POSITIVE

AND NEGATIVE FOR NOTCH1 MUTATION

SUMMARY

• Activation of Notch is a frequent event in T-ALL

• Notch mutations are found in >50% of pediatric and adult T-ALLs

• Inhibition of gamma-secretase activity results in inhibition of leukemia cell Notch signaling.

• Use of gamma-secretase inhibitors is a rational approach to the therapy of T-ALL

SOURCESAcute Lymphocytic Leukemia. (n.d.). Retrieved March 2015.

Chiaretti S, Foà R. T-cell acute lymphoblastic leukemia. Haematologica. 2009;94(2):160-162. doi:10.3324/haematol.2008.004150.

Grabher, C., von Boehmer, H., & Look, A. T. (2006). Notch 1 activation in the molecular pathogenesis of T-cell acute lymphoblastic leukaemia. Nature Reviews Cancer, 6(5), 347-359.

How is childhood leukemia classified? (n.d.). Retrieved March 2015.

Radtke, F., & Raj, K. (2003). The role of Notch in tumorigenesis: oncogene or tumour suppressor?. Nature Reviews Cancer, 3(10), 756-767.

Sun W, Gaykalova DA, Ochs MF, et al. Activation of the NOTCH pathway in Head and Neck Cancer. Cancer research. 2014;74(4):1091-1104. doi:10.1158/0008-5472.CAN-13-1259.

Swiatek, P. J., Lindsell, C. E., Del Amo, F. F., Weinmaster, G., & Gridley, T. (1994). Notch1 is essential for postimplantation development in mice. Genes & development, 8(6), 707-719.

Weinberg, Robert A. The Biology of Cancer. New York: Garland Science, 2014. Print.

Zhu, Y. M., Zhao, W. L., Fu, J. F., Shi, J. Y., Pan, Q., Hu, J., ... & Chen, S. J. (2006). NOTCH1 mutations in T-cell acute lymphoblastic leukemia: prognostic significance and implication in multifactorial leukemogenesis. Clinical Cancer Research, 12(10), 3043-3049.