Stat3: A Direct Hmga1 Gene Target Important In Lymphoid Malignancy.

While the oncogenic properties of the high mobility group A1 (HMGA1) gene are well established, the molecular pathways that mediate transformation by HMGA1 have not been clearly defined. HMGA1 is widely overexpressed in hematologic malignancies and other human cancers. Moreover, its overexpression portends a poor prognosis in some tumors. The HMGA1 gene encodes the HMGA1a and -A1b chromatin binding proteins. We previously showed that overexpression of HMGA1a or -A1b confers a transformed phenotype in cultured, human lymphoid cells. More recently, we developed transgenic mice overexpressing HMGA1a and all mice develop aggressive lymphoid malignancy. Because HMGA1 proteins function in regulating gene expression, we hypothesize that overexpression of HMGA1 leads to neoplastic transformation by altering expression of specific target genes involved in this process. To identify genes that are regulated by HMGA1 in transformation, we used microarray gene expression profile analysis in cells transfected to overexpress HMGA1a or -A1b. Ninety-seven genes were differentially regulated by ≥ 2-fold in cells overexpressing HMGA1a and 103 genes were differentially regulated by ≥ 2-fold in cells overexpressing HMGA1b. Fifty-five of these genes were common to both the HMGA1a and -A1b cells. From the list of genes up-regulated in cells overexpressing HMGA1a or A1b, the gene encoding the signaling molecule, signal transducer and activator of transcription or STAT3, was studied further because of its prominent role in malignancy. HMGA1 binds to the STAT3 promoter in human leukemia cells in vivo by chromatin immunoprecipitation experiments and enhances transcription of the STAT3 promoter in transfection experiments. Both total STAT3 and activated STAT3 proteins are increased in leukemia cells from HMGA1a transgenic mice compared to lymphoid cells from control mice. Moreover, activated STAT3 recapitulates the transforming activity of HMGA1a in cultured cells. Blocking STAT3 function preferentially induces apoptosis in leukemia cells from HMGA1a transgenic mice, but not in control cells. STAT3 mRNA is also increased in human acute lymphoid leukemia samples that overexpress HMGA1a, suggesting that this pathway is also involved in human lymphoid leukemia. Our results indicate that STAT3 is a direct HMGA1a target gene that is both necessary and sufficient for transformation induced by HMGA1a.