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

Abstract

BackgroundAlthough 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.ResultsRNA 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.ConclusionsWe 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.

IBRUTinib: BRUTe force against bortezomib-resistant myeloma cells

“…3 Emerging evidence suggests that master regulators, such as the high mobility group A1 (HMGA1) chromatin remodeling protein, orchestrates the assembly of Nuclear-factor kappa B (NF-kB) and transcription factor complexes to induce stem cell transcriptional networks and downstream signaling pathways that maintain CSCs. [3][4][5][6] Prior studies also suggest that Nuclear-factor kappa B (NF-kB) is hyperactive in MM and leukemic stem cells (Fig. 1).…”

HMGA1 Drives Metabolic Reprogramming of Intestinal Epithelium during Hyperproliferation, Polyposis, and Colorectal Carcinogenesis

“…Gene expression profile analyses demonstrate that HMGA1 drives tumor progression and stem cell properties through transcriptional networks expressed in pluripotent stem cells and developing embryos. 18,[21][22][23] Recently, the metabolic profiles of primary CR tumors and adjacent, nonmalignant tissue have been examined using several techniques, including: magic angle spinning -nuclear magnetic resonance (MAS-NMR), gas chromatography -mass spectrometry (GC-MS), ultra-performance liquid chromatography -quadrupole time-of-flight mass spectrometry (UPLC-QToF-MS) and capillary electrophoresis -MS (CE-MS). [24][25][26][27][28][29][30][31][32][33][34] Other platforms used to investigate metabolomes from urine or serum of patients with CRC include GC-MS, UPLC-QToF-MS (MS/MS), Fourier transform ion-cyclotron-MS (FTICR-MS) and proton NMR ( 1 H-NMR).…”

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

“…This finding suggests that uterine tumors induced by HMGA1 in this model are dependent on MMP-2 for growth at the stage in which we measured tumor size, in contrast to the lymphoid tumors, which may depend on other HMGA1 pathways [10, 12, 21-22]. In primary human carcinosarcomas, we also found a positive correlation between HMGA1 and MMP -2, but only in a subset of these tumors.…”