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Alena Yermalovich

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National Institutes of Health (NIH)
LIN28B is a highly conserved RNA-binding protein that is involved in development, stem cell biology, control of glucose metabolism, and tumorigenesis. It regulates one of the most ancient and highly conserved microRNA (miRNA) families, let-7, by blocking their processing into mature miRNAs. Activation of LIN28B has been documented in a growing list of various cancers, especially those that are highly aggressive and poorly differentiated. Our laboratory recently discovered that mice overexpressing LIN28B in the kidneys during nephrogenesis develop a malignancy highly reminiscent of the most common renal neoplasm of childhood, Wilms' tumor. Wilms' tumor arises from pluripotent embryonic kidney precursor cells and is associated with persistent embryonic renal tissue. Prior studies have implicated that loss of the WT1 tumor suppressor leads to Wilms tumors, but WT1 deficiency accounts for less than a third of all tumors. Our studies have implicated LIN28B as a novel pathway, and in this application I propose to study LIN28B in both normal kidney development and tumorigenesis. It is my hope that discovery of Wilms' specific pathways or targets would add considerable depth to our mechanistic understanding of LIN28B tumorigenesis and may be important for defining therapeutic approaches. The importance of LIN28B in tumorigenesis is readily appreciated and one of major focuses of the field has been to understand the mechanisms that underlie LIN28B upregulation in human cancers. Previous studies concentrated on genomic amplification and aberrant hypomethylation of LIN28B loci as possible mechanisms of activation of the gene in tumors. It's been shown that while these genetic and epigenetic alterations indeed occur in a small subset of cancers, they are unlikely to be dominant mechanisms of LIN28B activation. Notably, several groups reported cases of Wilms' tumor with a chromosomal translocation involving the band in which LIN28B is located. When two Wilms' tumor cases carrying translocations were analyzed, they showed notably increased expression of LIN28B in the tumor samples compared with normal kidneys. Therefore, I hypothesize that LIN28B may be activated by chromosomal translocation to drive oncogenesis in some case. Study of the translocation might provide an endogenous, mutation-based mechanism of LIN28B activation, as it occurs in human patients and help to expose new potential targets for diagnosis and therapy.

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