notch-1 pre-t-cell acute lymphoblastic leukemias
TRANSCRIPT
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NOTCH-1
PR
E- T
- CE
L L AC
UT
E L
YM
PH
OB
L AS
TI C
LE
UK
EM
I AS
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NOTCH WAS FIRST IDENTIFIED IN THE FRUIT FLY DROSOPHILA
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NOTCH SIGNALING REGULATES MULTIPLE ASPECTS OF INVERTEBRATE AND VERTEBRATE
DEVELOPMENT.
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WHAT HAPPENS TO A MOUSE THAT LACKS NOTCH 1?
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NOTCH IS REQUIRED FOR T-CELL PROGENITORS OF THE AB LINEAGE TO
PROGRESS PAST THE DN3 B SELECTION CHECKPOINT FOR T-CELL DEVELOPMENT
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NOTCH ENCODES A CELL SURFACE RECEPTORWITH A TRANSMEMBRANE-BOUND LIGAND
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UPON LIGAND BINDING, NOTCH IS PROTEOLYTICALLY CLEAVED AND THE
CYTOPLASMIC FRAGMENTACTS AS A TRANSCRIPTION FACTOR
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NOTCH1 GENE IN GENOMIC LOCATION
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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%
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CHROMOSOMAL TRANSLOCATION LEADING TO T-ALL
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THE T(7;9)(Q34;Q34.3) TRANSLOCATION, WHICH OCCURS IN ~1% OF T-ALL, LEADS TO THE CONSTITUTIVE EXPRESSION OF
ACTIVE NOTCH1
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NOTCH1 MUTATIONS HAVE BEEN REPORTED TO OCCUR IN 10 TO 15% OF
HEAD AND NECK SQUAMOUS CELL CARCINOMAS (HNSCC)
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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
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IDENTIFICATION OF GENETIC ABERRATIONS, SUCH AS NOTCH1, IS IMPORTANT IN AN ATTEMPT TO DESIGN NOVEL FORMS OF
TARGETED THERAPIES.
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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
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A NOTABLE DIFFERENCE OF RELAPSE-FREE SURVIVAL EXISTS BETWEEN PATIENTS POSITIVE
AND NEGATIVE FOR NOTCH1 MUTATION
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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
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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.