NOTCH-1 PRE-T-CELL ACUTE LYMPHOBLASTIC LEUKEMIAS

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  LINEAGE TO PROGRESS PAST THE DN3  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 SubtypeFrequency Early Pre-B cell60%- 65% Pre-B cell20%- 25% Mature B cell2%- 3% T cell15%- 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 % of adults with ALL can expect to achieve full remission with standard treatments, and % 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 Chiaretti S, Foà R. T-cell acute lymphoblastic leukemia. Haematologica. 2009;94(2): doi: /haematol 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), How is childhood leukemia classified? (n.d.). Retrieved March Radtke, F., & Raj, K. (2003). The role of Notch in tumorigenesis: oncogene or tumour suppressor?. Nature Reviews Cancer, 3(10), Sun W, Gaykalova DA, Ochs MF, et al. Activation of the NOTCH pathway in Head and Neck Cancer. Cancer research. 2014;74(4): doi: / CAN 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), Weinberg, Robert A. The Biology of Cancer. New York: Garland Science, 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),