Tumorigenesis is a complex, multigenic process that leads to cell transformation and ultimately to the development of malignancy. Defining the molecular events that initiate and drive oncogenesis, and those that are required to maintain the malignant state, remain a formidable task. As a discovery tool to interrogate transcriptional networks involved in cancer, I have developed, tested and validated an innovative mammalian cell-based screening technology that allows one to define functional interactions between oncogenes or tumor suppressors and proteins implicated in transcriptional control. This technology allows one to integrate gene expression data with transcription factor activity, by defining the upstream transcriptional regulators responsible for gene activation. In applying this new technology, I identified a functional interaction between the oncoprotein CRTC1/MAML2, which is generated by the recurrent t(11;19)(q21;p13.1) chromosomal translocation that fuses the CREB coactivator CRTC1 to the NOTCH coactivator MAML2, and the oncogene MYC. Further, my Preliminary Studies strongly suggest that the CRTC1/MAML2 oncoprotein hijacks the Myc network to drive cell transformation and tumorigenesis. These findings challenge the existing paradigm that chimeric oncoproteins display functional characteristics related solely to their constituent parent molecules. Given these findings, I hypothesize that CREB and MYC transcription factor networks cooperate in oncogenesis. Genetic approaches using validated models of B cell lymphoma will be used to test this hypothesis, where I will assess the relevance and define the mechanism(s) of CRTC1/MAML2 interactions with MYC and the role of CRTCs in driving cell transformation, lymphomagenesis, and the maintenance of the malignant state.)

Public Health Relevance

Cancers were the second leading cause of death in the United States in 2009 (559,888 deaths) with 28% due to lung and bronchus cancers and 8% due to leukemia and lymphoma;a subset of these primary lung and lymphoma tumors share a common t(11;19)(q21;p13.1) translocation that creates a chimeric CRTC1/MAML2 oncoprotein that we discovered coordinates the CRTC:CREB and MYC:MAX networks. Using a validated mouse model of human B cell lymphoma and leukemia, the goals of the proposed K99/R00 research are to study the role of the Myc:Max pathway in CRTC1/MAML2-mediated oncogenesis and critically assess the role of the CTRC:CREB pathway in cooperating with Myc to drive tumorigenesis, and in the maintenance of Myc- induced lymphoma. Since CREB regulates key aspects of cell survival and Myc is activated in up to 70% of all cancers, our discovery may provide the foundation for developing new agents that are broadly effective in cancer prevention and treatment.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Career Transition Award (K99)
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Study Section
Subcommittee G - Education (NCI)
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Schmidt, Michael K
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Scripps Florida
United States
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Cao, Chunxia; Gao, Ruli; Zhang, Min et al. (2015) Role of LKB1-CRTC1 on glycosylated COX-2 and response to COX-2 inhibition in lung cancer. J Natl Cancer Inst 107:358
Doherty, Joanne R; Yang, Chunying; Scott, Kristen E N et al. (2014) Blocking lactate export by inhibiting the Myc target MCT1 Disables glycolysis and glutathione synthesis. Cancer Res 74:908-20
Fallahi, Mohammad; Amelio, Antonio L; Cleveland, John L et al. (2014) CREB targets define the gene expression signature of malignancies having reduced levels of the tumor suppressor tristetraprolin. PLoS One 9:e115517
Bruno, Nelson E; Kelly, Kimberly A; Hawkins, Richard et al. (2014) Creb coactivators direct anabolic responses and enhance performance of skeletal muscle. EMBO J 33:1027-43
Amelio, Antonio L; Fallahi, Mohammad; Schaub, Franz X et al. (2014) CRTC1/MAML2 gain-of-function interactions with MYC create a gene signature predictive of cancers with CREB-MYC involvement. Proc Natl Acad Sci U S A 111:E3260-8