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.
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.
|Fabbri, Giulia; Holmes, Antony B; Viganotti, Mara et al. (2017) Common nonmutational NOTCH1 activation in chronic lymphocytic leukemia. Proc Natl Acad Sci U S A 114:E2911-E2919|
|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|
|Rossi, Davide; Rasi, Silvia; Spina, Valeria et al. (2013) Integrated mutational and cytogenetic analysis identifies new prognostic subgroups in chronic lymphocytic leukemia. Blood 121:1403-12|