Transcription Factor GFI1B in Health and Disease

Abstract

Many human diseases arise through dysregulation of genes that control key cell fate pathways. Transcription factors (TFs) are major cell fate regulators frequently involved in cancer, particularly in leukemia. The GFI1B gene, coding a TF, was identified by sequence homology with the oncogene growth factor independence 1 (GFI1). Both GFI1 and GFI1B have six C-terminal C2H2 zinc fingers and an N-terminal SNAG (SNAIL/GFI1) transcriptional repression domain. Gfi1 is essential for neutrophil differentiation in mice. In humans, GFI1 mutations are associated with severe congenital neutropenia. Gfi1 is also required for B and T lymphopoiesis. However, knockout mice have demonstrated that Gfi1b is required for development of both erythroid and megakaryocytic lineages. Consistent with this, human mutations of GFI1B produce bleeding disorders with low platelet count and abnormal function. Loss of Gfi1b in adult mice increases the absolute numbers of hematopoietic stem cells (HSCs) that are less quiescent than wild-type HSCs. In keeping with this key role in cell fate, GFI1B is emerging as a gene involved in cancer, which also includes solid tumors. In fact, abnormal activation of GFI1B and GFI1 has been related to human medulloblastoma and is also likely to be relevant in blood malignancies. Several pieces of evidence supporting this statement will be detailed in this mini review.

Keywords: GFI1B; cancer; hematopoiesis; leukemia; platelets disease.

Figure 1

Schematic representation of human growth factor independence 1 (GFI1) and GFI1B genes and corresponding protein domains: (A) diagram of human GFI1 locus and protein. On top, the black horizontal line represents the DNA sequence, red boxes on the sequence are coding GFI1 exons (Ex), and white boxes indicate UTRs. Underneath, GFI1 protein domains are indicated (green crescent represents the SNAG domain, and orange boxes are zinc fingers), the numbers over the blue rule indicate the amino acid positions; (B) GFI1B locus and long protein isoforms are depicted as in panel (A). The zigzag lines joining the Ex represent the splicing. Known mutations are shown on the protein and briefly described [acute myeloid leukemia (AML)]. (C) Short GFI1B splice variant and protein represented as in panels (A,B).

Figure 2

Differential expression of growth factor independence 1 (GFI1) and GFI1B during hematopoiesis. Upward pointing black arrows indicate high expression, and downward pointing black arrows represent low expression. The long and short GFI1B isoforms are represented as in Figure 1. The blue arrows indicate a positive impact on cell differentiation, and the red line reflects an inhibitory effect. Several evidences point to the role of GFI1B mutations and increase expression of the short variant in leukemogenesis (dashed arrow). HSC, hematopoietic stem cell; MPP, multipotent progenitor; CMP, common myeloid progenitor; MEP, megakaryocyte and erythroid progenitor; GMP, granulocyte and monocyte progenitor; CLP, common lymphoid progenitor.