Regulation of HIF-1 and tumor angiogenesis by PML and PML-RARa

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DESCRIPTION (provided by applicant): This proposal describes a five-year training program for the development of an academic career in Cancer Biology. I have seven years experience as a molecular biologist working in cancer research and I am now planning to expand my skills by utilizing mouse models of solid tumors and leukemias. In the first part of the program, I will be mentored by Dr. Pier Paolo Pandolfi, a leading cancer biologist who has great experience in modeling cancer in vivo and who has trained numerous independent investigators. The program will be enriched by the collaboration of Dr. C. Cordon-Cardo, Dr. S. Rafii and Dr. C. Simon. The first part of the award will be completed at Memorial Sloan-Kettering Cancer Center, a scientific environment of excellence that will provide all the resources necessary to promote the success of this Career Development Award. Research will focus on the study of the regulation of HIF-1 and tumor angiogenesis by the promyelocytic leukemia gene PML, and the fusion protein of acute promyelocytyc leukemia (API), PML RARa. The transcription factor HIF-1 is the main regulator of cellular responses to hypoxia. HIF-1 is frequently upregulated in solid tumors and fosters tumor progression by promoting neoangiogenesis. Conversely, PML is frequently lost in solid tumors. My preliminary observations indicate that PML is a negative regulator of HIF-1. Accordingly, Pml-/- cells have higher HIF-1 activity than wild-type cells when subjected to hypoxic stimuli and Pml-/- mice have increased neoangiogenesis in response to ischemia. Finally, I have found that PML-RARa acts as a constitutive transcriptional co-activator of HIF-1. This observation supports the novel concept that neoangiogenesis in the bone marrow is an important process in leukemogenesis. In this proposal, I aim at answering the following questions: What is the molecular mechanism by which PML regulates HIF-1? What is the effect of PML loss in the process of neoangiogenesis in solid tumors? And, finally, is HIF activity important in the development of APL? I will address these questions in the following specific aims: 1. Elucidate the molecular mechanisms of HIF-1 a regulation by PML; 2. Study the effect of PML loss on tumor angiogenesis and tumor progression in vivo; 3. Study the role of HIF-1a overexpression in leukemia in mouse models of APL. The Training Program outlined in this proposal will launch my independent research career.