A recent study found activating Notch1 mutations in 55% of human T-ALL patient samples. These newly discovered mutations are distributed among two hotspots -- the heterodimerization (HD) and PEST domains. However, the relative importance and consequence of each mutation remains unknown and unexplored. My preliminary research suggests that a single activating mutation in the HD hotspot cannot induce T-ALL in mice unless a second mutation occurs in the PEST hotspot in cis. I will follow up on these observations by determining whether all HD mutations require concurrent PEST mutations and by identifying cooperating oncogenes during the multi-step pathogenesis of T-ALL. In order to understand the molecular mechanism by which Notch initiates and sustains oncogenesis, I will characterize the effect of Notch inhibition on the proliferation, survival, and differentiation of leukemic cell lines and use this information to develop a systematic strategy for testing putative target genes generated from microarray data sets. Together these studies should not only lead to an improved understanding of T-ALL pathogenesis but will also identify novel therapeutic strategies for treatment. This proposal describes a 5 year training program to develop an academic career in cancer biology. The experiments described in the proposal will provide valuable experience in the use and manipulation of murine genetic model systems for the study of cancer under the mentorship of Dr. Warren Pear. Dr. Pear is an associate professor at the Abramson Family Cancer Research Institute with extensive experience in the manipulation and analysis of animal models of leukemogenesis. Ultimately, the time spent in the development of this project will establish a line of inquiry in the field of leukemogenesis and will provide the skills necessary to establish myself as a successful physician scientist and independent researcher. Acute T cell lymphoblastic leukemia remains a deadly cancer in children and adults which cannot be cured in more than one out of every three to four patients. A recent breakthrough study has identified Notch1 mutations in the majority of patients with this cancer. My research seeks to uncover the significance of these mutations and the cancer-causing molecular events in the cell that are triggered by this mutation, which may provide new opportunities for therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08CA120544-04
Application #
7653806
Study Section
Subcommittee G - Education (NCI)
Program Officer
Myrick, Dorkina C
Project Start
2006-06-01
Project End
2009-12-31
Budget Start
2009-06-01
Budget End
2009-12-31
Support Year
4
Fiscal Year
2009
Total Cost
$133,272
Indirect Cost
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Pinnell, Nancy E; Chiang, Mark Y (2013) Collaborating Pathways that Functionally Amplify NOTCH1 Signals in T-Cell Acute Lymphoblastic Leukemia. J Hematol Transfus 1:
Chiang, Mark Y; Shestova, Olga; Xu, Lanwei et al. (2013) Divergent effects of supraphysiologic Notch signals on leukemia stem cells and hematopoietic stem cells. Blood 121:905-17
Giambra, Vincenzo; Jenkins, Christopher R; Wang, Hongfang et al. (2012) NOTCH1 promotes T cell leukemia-initiating activity by RUNX-mediated regulation of PKC-? and reactive oxygen species. Nat Med 18:1693-8
Liu, Hudan; Chiang, Mark Y; Pear, Warren S (2011) Critical roles of NOTCH1 in acute T-cell lymphoblastic leukemia. Int J Hematol 94:118-125
Liu, Hudan; Chi, Anthony W S; Arnett, Kelly L et al. (2010) Notch dimerization is required for leukemogenesis and T-cell development. Genes Dev 24:2395-407
Chiang, Mark Y; Xu, Lanwei; Shestova, Olga et al. (2008) Leukemia-associated NOTCH1 alleles are weak tumor initiators but accelerate K-ras-initiated leukemia. J Clin Invest 118:3181-94