The HMG-I/Ygene encodes the HMG-I and -Y protein isoforms, which function as architectural chromatin binding proteins involved in transcriptional regulation. These proteins are up-regulated in human cancer, although their role in the pathogenesis of malignancy is unclear. To understand how HMG-I/Y proteins may contribute to transformation, we are exploring their regulation and function. We discovered that HMG-I/Y is a direct c-Myc target gene important in Burkitt's lymphoma. We also demonstrated that HMG-I/Y is necessary for transformation because decreasing these proteins in human cancer cell lines blocks the transformed phenotype. We were the first to show that HMG-I/Y proteins have several oncogenic properties. Specifically, overexprossion of HMG-I or-Y leads to anchorage-independent cell growth in several experimental cell lines. Fibroblasts overexpressing HMG-I or-Y are tumorigenic in nude mice. We developed transgenic mice overexpressing HMG-/in lymphoid cells and all of them develop lymphoid hyperplasia and malignancy at a mean age of 8 months. HMG-I overexpression also correlates with genomic instability, which may contribute to tumor initiation or progression. Thus, I hypothesize that HMG-I/Y is an oncogene important in the pathogenesis of human cancer. The focus of this research proposal is to identify the mechanisms involved in transformation by HMG-I/Y using unique reagents developed in my laboratory.
Our Specific Aims Are: 1.) Identify and characterize direct HMG-I/Y gene targets involved in neoplastic transformation using microarray analysis. 2.) Define the functional domains of HMG-I/Y involved in transformation, chromosomal instability, and cell cycle regulation. A.) Identify the functional domains of HMG-I/Y required for transformation using the soft agar transformation assay. B.) Investigate the role of HMGI/ Y in genomic instability and identify the relevant domains using spectral karyotyping analysis. C.) Investigate the role of HMG-I/Y in cell cycle regulation and identify the relevant domains using cell cycle profile analysis. 3.) Define the pathways involved in transformation using our HMG-I transgenic mice. A.) Assess transformed lymphoid cells from the HMG-I trangenic mice for overexpression of HMG-I target genes and chromosomal instability B.) Identify pathways involved in transformation by HMG-I by crossing the HMG-I transgenic mice with other genetically altered mice. 4.) Determine if HMG-I/Yexpression correlates with prognosis and clinical outcome in lymphoid malignancies and brain tumors. Study HMG-I/Y gene and protein expression in patient samples from the Johns Hopkins Leukemia and Brain Tumor Banks. This proposal is significant because the results will enhance our understanding of human malignancies with increased HMG-I/Y proteins and may lead to new treatment strategies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA092339-02
Application #
6767574
Study Section
Pathology B Study Section (PTHB)
Program Officer
Mufson, R Allan
Project Start
2003-07-01
Project End
2007-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
2
Fiscal Year
2004
Total Cost
$291,030
Indirect Cost
Name
Johns Hopkins University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Hillion, Joelle; Roy, Sujayita; Heydarian, Mohammad et al. (2016) The High Mobility Group A1 (HMGA1) gene is highly overexpressed in human uterine serous carcinomas and carcinosarcomas and drives Matrix Metalloproteinase-2 (MMP-2) in a subset of tumors. Gynecol Oncol 141:580-587
Belton, Amy; Xian, Lingling; Huso, Tait et al. (2016) STAT3 inhibitor has potent antitumor activity in B-lineage acute lymphoblastic leukemia cells overexpressing the high mobility group A1 (HMGA1)-STAT3 pathway. Leuk Lymphoma 57:2681-4
Sumter, T F; Xian, L; Huso, T et al. (2016) The High Mobility Group A1 (HMGA1) Transcriptome in Cancer and Development. Curr Mol Med 16:353-93
Roy, Sujayita; Di Cello, Francescopaolo; Kowalski, Jeanne et al. (2013) HMGA1 overexpression correlates with relapse in childhood B-lineage acute lymphoblastic leukemia. Leuk Lymphoma 54:2565-7
Shah, Sandeep N; Cope, Leslie; Poh, Weijie et al. (2013) HMGA1: a master regulator of tumor progression in triple-negative breast cancer cells. PLoS One 8:e63419
Di Cello, Francescopaolo; Dhara, Surajit; Hristov, Alexandra C et al. (2013) Inactivation of the Cdkn2a locus cooperates with HMGA1 to drive T-cell leukemogenesis. Leuk Lymphoma 54:1762-8
Hillion, Joelle; Smail, Shamayra S; Di Cello, Francescopaolo et al. (2012) The HMGA1-COX-2 axis: a key molecular pathway and potential target in pancreatic adenocarcinoma. Pancreatology 12:372-9
Shah, Sandeep N; Resar, Linda M S (2012) High mobility group A1 and cancer: potential biomarker and therapeutic target. Histol Histopathol 27:567-79
Belton, Amy; Gabrovsky, Alexander; Bae, Young Kyung et al. (2012) HMGA1 induces intestinal polyposis in transgenic mice and drives tumor progression and stem cell properties in colon cancer cells. PLoS One 7:e30034
Schuldenfrei, Andrew; Belton, Amy; Kowalski, Jeanne et al. (2011) HMGA1 drives stem cell, inflammatory pathway, and cell cycle progression genes during lymphoid tumorigenesis. BMC Genomics 12:549

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