Critical role of the high mobility group A proteins in hematological malignancies

Abstract

The high mobility group A (HMGA) protein family is composed of three non-histone chromatin remodeling proteins that act as architectural transcriptional factors. Indeed, although HMGA proteins lack transcriptional activity per se, they bind the minor groove of DNA at AT-rich sequences, and, interacting with the transcription machinery, are able to modify chromatin modeling, thus regulating the expression of several genes. HMGA proteins have been deeply involved in embryogenesis process, and a large volume of studies has pointed out their key role in human cancer. Here, we review the studies on the role of the HMGA proteins in human hematological malignancies: they are overexpressed in most of the cases and their expression correlates with a reduced survival. In some cases, such as in acute lymphoblastic leukemia and acute myelogenous leukemia, HMGA2 gene rearrangements have been also described. Finally, recent studies evidence a synergism between HMGA and EZH2 in diffuse B-cell lymphomas, suggesting an innovative therapy for this disease based on the inhibition of the function of both these proteins.

Keywords: EZH2; HMGA1; HMGA1 pseudogenes; HMGA2; hematological malignancies.

FIGURE 1

Main molecular mechanisms by which high mobility group A proteins are involved in human cancer. Created with BioRender.com

FIGURE 2

High mobility group A protein roles in myeloid and lymphoid neoplasms. Created with BioRender.com

FIGURE 3

HMGA1 is able to bind Enhancer of Zeste Homolog 2 promoter region and upregulate its expression levels in human lymphomas. Created with BioRender.com