Leukemia and lymphoma are common, frequently lethal human cancers. To better understand how lymphoid malignancies develop, we are identifying molecular pathways that give rise to transformation in lymphoid cells. Our focus is the HMG-I oncogene because preliminary studies suggest that it plays an important role in the pathogenesis of lymphoid cancers. The HMG-I/Y gene encodes the HMG-I and -Y chromatin binding proteins, which function in regulating gene expression. The Resar lab showed that: 1.) HMG-I/Y is a downstream gene target activated by c-Myc and important in neoplastic transformation. 2.) HMG-I is up-regulated in aggressive leukemia cells compared to normal lymphoid cells, 3) High levels of HMG-I mRNA correlate with relapse in B-cell leukemia, 4.) Forced overexpression of HMG-I in normal lymphoid cells confers a transformed phenotype, 5.) Inhibiting HMG-I/Y expression blocks the transformed phenotype in leukemia cells, and, 6.) All HMG-I transgenic mice develop aggressive leukemia which recapitulates the salient features of human acute lymphocytic leukemia. Using our unique resources, we are now investigating downstream microRNAs (miRNAs) dysregulated by HMG-I. miRNAs are ~22 nucleotide non-protein-coding RNAs that regulate gene expression. An increasing body of evidence suggests that miRNA dysfunction is a critical event in lymphoid tumorigenesis, although the miRNAs dysregulated by HMG-I have not been investigated. In preliminary studies, we showed that the mir-150 miRNA is down-regulated in lymphoid tumors from our HMG-I transgenic mice. The mir-150 microRNA is highly-expressed in mature B and T cells, but not in hematopoietic stem cells, suggesting a potential role in lymphoid cell differentiation. Consistent with these findings, a recent study showed that mir-150 is involved in B cell differentiation. Thus, we hypothesize that HMG-I contributes to lymphoid malignancy by disrupting regulation of specific miRNAs and their downstream molecular pathways. Using the novel reagents developed in the Resar laboratory, I propose to elucidate these miRNAs and pathways.
My Specific Aims are: 1.) Define the functional significance of mir-150 in lymphoid transformation induced by HMG-I. 2.) Identify and characterize additional miRNAs disrupted by HMG-I in lymphoid transformation using microRNA profile analysis. Results from these studies will enhance our understanding of the pathogenesis of lymphoid malignancies and may ultimately lead to the discovery of novel therapeutic targets. This funding will also provide me with the opportunity to pursue my graduate studies in this exciting field as well as expand the pool of under-represented minority scientists.
