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Open Access Research article

HMGA1 drives stem cell, inflammatory pathway, and cell cycle progression genes during lymphoid tumorigenesis

Andrew Schuldenfrei1, Amy Belton1, Jeanne Kowalski2, C Conover Talbot3, Francescopaolo Di Cello1, Weijie Poh14, Hua-Ling Tsai2, Sandeep N Shah1, Tait H Huso1, David L Huso56 and Linda MS Resar167*

  • * Corresponding author: Linda MS Resar lresar@jhmi.edu

  • † Equal contributors

Author Affiliations

1 Department of Medicine, Division of Hematology, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD, 21205, USA

2 Department of Oncology, Division of Oncology Biostatistics, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 550 North Broadway, Baltimore, MD 21205, USA

3 Institute for Basic Biomedical Sciences, Johns Hopkins University School of Medicine, 733 North Broadway, Baltimore, MD, 21205, USA

4 Pathobiology Graduate Program, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD, 21205, USA

5 Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, 733 North Broadway, Baltimore, MD, 21205, USA

6 Department of Oncology, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD 21205, USA

7 Department of Pediatrics, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, Maryland 21205

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BMC Genomics 2011, 12:549  doi:10.1186/1471-2164-12-549

Published: 4 November 2011

Abstract

Background

Although the high mobility group A1 (HMGA1) gene is widely overexpressed in diverse cancers and portends a poor prognosis in some tumors, the molecular mechanisms that mediate its role in transformation have remained elusive. HMGA1 functions as a potent oncogene in cultured cells and induces aggressive lymphoid tumors in transgenic mice. Because HMGA1 chromatin remodeling proteins regulate transcription, HMGA1 is thought to drive malignant transformation by modulating expression of specific genes. Genome-wide studies to define HMGA1 transcriptional networks during tumorigenesis, however, are lacking. To define the HMGA1 transcriptome, we analyzed gene expression profiles in lymphoid cells from HMGA1a transgenic mice at different stages in tumorigenesis.

Results

RNA from lymphoid samples at 2 months (before tumors develop) and 12 months (after tumors are well-established) was screened for differential expression of > 20,000 unique genes by microarray analysis (Affymetrix) using a parametric and nonparametric approach. Differential expression was confirmed by quantitative RT-PCR in a subset of genes. Differentially expressed genes were analyzed for cellular pathways and functions using Ingenuity Pathway Analysis. Early in tumorigenesis, HMGA1 induced inflammatory pathways with NFkappaB identified as a major node. In established tumors, HMGA1 induced pathways involved in cell cycle progression, cell-mediated immune response, and cancer. At both stages in tumorigenesis, HMGA1 induced pathways involved in cellular development, hematopoiesis, and hematologic development. Gene set enrichment analysis showed that stem cell and immature T cell genes are enriched in the established tumors. To determine if these results are relevant to human tumors, we knocked-down HMGA1 in human T-cell leukemia cells and identified a subset of genes dysregulated in both the transgenic and human lymphoid tumors.

Conclusions

We found that HMGA1 induces inflammatory pathways early in lymphoid tumorigenesis and pathways involved in stem cells, cell cycle progression, and cancer in established tumors. HMGA1 also dyregulates genes and pathways involved in stem cells, cellular development and hematopoiesis at both early and late stages of tumorigenesis. These results provide insight into HMGA1 function during tumor development and point to cellular pathways that could serve as therapeutic targets in lymphoid and other human cancers with aberrant HMGA1 expression.