GATA-2 mediated regulation of normal hematopoietic stem/progenitor cell function, myelodysplasia and myeloid leukemia

Abstract

Unremitting blood cell production throughout the lifetime of an organism is reliant on hematopoietic stem cells (HSCs). A rare and relatively quiescent cell type, HSCs are, on entry into cell cycle fated to self-renew, undergo apoptosis or differentiate to progenitors (HPCs) that eventually yield specific classes of blood cells. Disruption of these HSC fate decisions is considered to be fundamental to the development of leukemia. Much effort has therefore been placed on understanding the molecular pathways that regulate HSC fate decisions and how these processes are undermined in leukemia. Transcription factors have emerged as critical regulators in this respect. Here we review the participation of zinc finger transcription factor GATA-2 in regulating normal hematopoietic stem and progenitor cell functionality, myelodysplasia and myeloid leukemia.

Fig. 1. Mouse and human GATA-2 gene structure

A. The mouse GATA-2 gene is on chromosome 6. There are two isoforms (IS, IG) of mouse GATA-2 and exon-intron organization is shown; exons and introns are spread over 8632 nucleotides. B. The human GATA-2 gene is located on chromosome 3. There are three isoforms (IS, IG, unnamed) of human GATA-2 and exon-intron organization is shown; exons and introns are spread over 13,579 base pair nucleotides.

Fig. 2

GATA-2 protein structure and post-translational modifications. The human and mouse GATA-2 genes encode proteins of between 466–480 amino acids. The GATA-2 protein contains 2 zinc fingers which serve as DNA binding domains and sites for protein-protein interaction (e.g partner protein binding). There are several sites of post-translational modifications including phosphorylation, acetylation, sumoylation and ubiquitination. Key: TAD= Transactivation domain, NRD = negative regulatory domain, nuclear localization domain and ZF= zinc fingers.