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Dissecting the Genome-wide Action of Interferon Regulatory Factor 4 (IRF4) in Melanoma (OncoGeneRegulation)
Date du début: 1 août 2011, Date de fin: 31 juil. 2015 PROJET  TERMINÉ 

Interferon regulatory factor 4 (IRF4) is a transcriptional regulator with critical roles in lymphocyte development and function. We have recently shown that cells from a poor-prognosis subtype of lymphoma and multiple myeloma show non-oncogene addiction to IRF4. Using integrative genome-wide strategies, we have identified the gene regulatory program that IRF4 controls in these cancers.In several studies, high IRF4 expression was consistently observed also in cells derived from the melanoma type skin cancers at both mRNA and protein level. A survey of multiple gene expression profiling studies show that IRF4 expression is significantly high in melanoma. In addition, several genome-wide association studies identified IRF4-linked polymorphisms contributing to pigmentation, nevi count and risk of developing melanoma. These studies, taken together with our first-hand understanding of IRF4’s crucial role in B-cell cancers, strongly implicate a direct role for IRF4 in melanoma. However, the extent and molecular mechanisms of the role of IRF4 in melanoma and melanocyte biology have so far not been reported.We are initiating a project to study the role of IRF4 in melanoma cells using cellular, molecular, and genome-wide approaches as the first segment of my research program aimed at investigating the critical gene regulatory and epigenetic networks in cancers. Specifically, we will study the requirement of IRF4 in the tumorigenicity of melanoma cells. Further, we aim to employ genome-wide expression and localization (ChIP-Seq) assays to identify the genes and downstream pathways controlled by IRF4 in melanoma, and test their roles in melanoma development and progression. Melanoma incidence has been on the rise, and advanced forms of melanoma are mostly resistant to current therapies, and deadly. This project is aimed at improving understanding of melanoma biology, and identification of novel genes and pathways that can ultimately be targeted for therapy.