Notch signaling is a highly conserved pathway which plays many critical roles throughout development, and is dysregulated during oncogenesis. The consequences of Notch signaling vary by cell type and depend on poorly characterized downstream mechanisms. We and others have observed contrasting roles for Notch in T and B lymphocytes and leukemias which share a common lymphoid precursor. In T cells, Notch promotes commitment and expansion, and constitutive activation leads to T cell proliferation and leukemogenesis. In contrast, Notch signaling inhibits B cell commitment and leads to growth arrest and apoptosis in normal and leukemic B cells. We have found that the Notch downstream gene HES1 is sufficient to induce growth arrest and apoptosis in B cell leukemias, but not T cell leukemias. These findings suggest that HES1 may play a critical role in determining the cell type- specific consequences of Notch signaling. The goal of this project is to elucidate the mechanism(s) by which HES1 alters the consequences of Notch signaling. We propose to use acute leukemia subtypes as a model for these cell-specific differences, and will characterize the role of HES1 in T cell versus B cell leukemias. Our results suggest that PARP1 interaction may be one mechanism, where PARP1 regulates HES1 function and leads to PARP1 cleavage and pro-apoptotic consequences. In addition, HES1 may have an alternate repertoire of transcriptional targets leading to divergent consequences.
In Aim 1 we define the cell context-dependent regulation of the HES1 transcriptional complex, with a novel role for PARP1 in altering HES1 function and ties HES1 to the apoptotic cascade.
Aim 2 characterizes the transcriptional consequences of HES1 signaling using genome-wide ChIP-SEQ and expression analysis, and characterization of two HES1-regulated genes which may contribute to Notch/HES1-mediated growth inhibition and apoptosis.
In Aim 3 we propose to validate our hypothesis in leukemia patient samples through characterization of Notch pathway activation and exploration of the effects of the Notch ligands on these patient samples. Defining the cell context-dependent differences across acute leukemia subtypes will provide important insights into the mechanisms behind the diverse roles of Notch. These insights will inform our understanding of Notch signaling in development and oncogenesis, and may allow us to """"""""tip-the-balance"""""""" from Notch-mediated oncogenesis to growth suppression, defining a new paradigm for cancer therapy.
Notch signaling has diverse roles in development and can have both oncogenic and tumor inhibiting effects. This project aims to uncover the mechanisms behind these different outcomes in acute leukemias. Insights into these mechanisms may allow us to tip-the-balance from oncogenesis to growth inhibition and apoptosis, defining a new approach for leukemia/cancer therapy.
|Kannan, Sankaranarayanan; Sutphin, Robert M; Hall, Mandy G et al. (2013) Notch activation inhibits AML growth and survival: a potential therapeutic approach. J Exp Med 210:321-37|
|Kannan, Sankaranarayanan; Fang, Wendy; Song, Guangchun et al. (2011) Notch/HES1-mediated PARP1 activation: a cell type-specific mechanism for tumor suppression. Blood 117:2891-900|