Chronic lymphocytic leukemia (CLL) is the most prevalent hematologic cancer in the US. Importantly, and in contrast with other hematologic malignancies, CLL responds only transiently to chemotherapy and there is no available curative therapy. Activating mutations in NOTCH1 have been recently found in 10-15% of CLL cases and are associated with poor prognosis, disease progression, chemotherapy resistance and transformation to diffuse large B cell lymphoma (DLBCL) (Fabbri et al., J Exp Med 2011;Puente et al, Nature 2011). Notably, NOTCH1 signaling can be effectively blocked with inhibitory antibodies and gamma-secretase inhibitors, currently under development as anti-NOTCH therapies for the treatment of cancer. Our central hypothesis is that NOTCH1 mutations may contribute to the pathogenesis of CLL by disrupting specific transcriptional programs that regulate cell proliferation, differentiation and survival in CLL cells. The goals of this research proposal are to define the molecular and cellular functions of NOTCH1 in CLL transformation, to analyze the oncogenic effects of mutant NOTCH1 in vivo, and to test the effects of NOTCH inhibition alone and in combination with chemotherapy in the treatment of CLL.

Public Health Relevance

This project aims to analyze the transcriptional targets and oncogenic pathways controlled by NOTCH1 in the pathogenesis of Chronic Lymphocytic Leukemia (CLL). The experiments outlined here will improve our understanding of the oncogenic mechanisms mediating NOTCH1- induced transformation and will set the basis for the rational development of new anti-NOTCH1 therapies against CLL.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA177319-02
Application #
8643783
Study Section
Special Emphasis Panel (ZRG1-OBT-H (03))
Program Officer
Howcroft, Thomas K
Project Start
2013-04-01
Project End
2018-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
2
Fiscal Year
2014
Total Cost
$347,566
Indirect Cost
$130,337
Name
Columbia University
Department
Pathology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Messina, Monica; Del Giudice, Ilaria; Khiabanian, Hossein et al. (2014) Genetic lesions associated with chronic lymphocytic leukemia chemo-refractoriness. Blood 123:2378-88
Fabbri, Giulia; Khiabanian, Hossein; Holmes, Antony B et al. (2013) Genetic lesions associated with chronic lymphocytic leukemia transformation to Richter syndrome. J Exp Med 210:2273-88