Chromosomal Translocations in Benign Tumors:The HMGI Proteins

Abstract

The high-mobility group (HMG) proteins are a family of nonhistone chromatin-associated proteins that have an important role in regulating chromatin architecture, as well as in regulating gene expression. The gene encoding one HMG protein, HMGI-C, is frequently rearranged or overexpressed by chromosomal translocations in common benign mesenchymal tumors including lipomas, leiomyomas, fibroadenomas, pleomorphic adenomas, aggressive angiomyxomas, and pulmonary hamartomas. The HMGI-C translocations involve many different translocation partners and are remarkable for their low risk of progression to malignancy.Since the initial recognition of the Philadelphia chromosome 1 and the subsequent identification of the BCR-ABL fusion gene resulting from the t(9;22), 2 a large number of chromosomal translocations have been identified in malignant human tumors. Much of the early progress in this field was in the area of hematologic malignant neoplasms.3-5 Cloning of the break points in these translocations led to the recognition of two general mechanisms of oncogenesis. Recently, another member of this subfamily, HMGKY), has also been shown to be rearranged in lipomas and pulmonary chondroid hamartomas. Given the high frequency of these benign mesenchymal tumors, it is likely that translocations involving the HMGI subfamily are one of the most common chromosomal rearrangements in human neoplasia. The HMG proteins are reviewed with an emphasis on the HMGI subfamily, and the potential role of these proteins in human tumorigenesis is discussed.

RAS and TGF-β exert antagonistic effects on extracellular matrix gene expression and fibroblast transformation

“…Among the genes induced during transformation, several lines of evidence implicate the HMGA1 gene (also known as HMG-I(Y)) in oncogenesis. First, the HMGA1 gene is the target of recurrent chromosomal translocations in several different types of benign tumors, and can induce anchorage-independent growth of Rat-1a cells (Hess, 1998;Kazmierczak et al, 1999;Wood et al, 2000). Second, it has functional properties, including the ability to regulate transcription, that are consistent with oncogenic potential.…”

The amino terminus of the mixed lineage leukemia protein (MLL) promotes cell cycle arrest and monocytic differentiation

“…These motifs appear to activate transcription by binding to AϩT-rich regions of DNA. Interestingly, translocations involving both HMGI-C and HMGI(Y) have been identified in a variety of benign mesenchymal tumors (14). The involvement of HMG proteins in tumorigenesis may be relevant to the function of MLL fusion proteins, because in all of these translocations the AT hook motifs are retained and are separated from the carboxyl-terminal portion of the protein (15).…”

The amino terminus targets the mixed lineage leukemia (MLL) protein to the nucleolus, nuclear matrix and mitotic chromosomal scaffolds

“…60). In particular, cytogenetic analysis indicated the possibility of a great number of alternative sequences positioned downstream of the three AT-hook motifs of HMGI-C in various rearrangements found in lipomas and other benign solid tumor types.…”