Download Notch-1

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 RECEPTOR
WITH A TRANSMEMBRANE-BOUND LIGAND
UPON LIGAND BINDING, NOTCH IS PROTEOLYTICALLY
CLEAVED AND THE CYTOPLASMIC FRAGMENT
ACTS 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
SOURCES
Acute 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.