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Review
. 2015 Dec 10;126(24):2561-9.
doi: 10.1182/blood-2015-06-655043. Epub 2015 Oct 7.

From cytopenia to leukemia: the role of Gfi1 and Gfi1b in blood formation

Tarik Möröy  1 , Lothar Vassen  2 , Brian Wilkes  3 , Cyrus Khandanpour  2
Affiliations
Review

From cytopenia to leukemia: the role of Gfi1 and Gfi1b in blood formation

Tarik Möröy et al. Blood. .

Abstract

The DNA-binding zinc finger transcription factors Gfi1 and Gfi1b were discovered more than 20 years ago and are recognized today as major regulators of both early hematopoiesis and hematopoietic stem cells. Both proteins function as transcriptional repressors by recruiting histone-modifying enzymes to promoters and enhancers of target genes. The establishment of Gfi1 and Gfi1b reporter mice made it possible to visualize their cell type-specific expression and to understand their function in hematopoietic lineages. We now know that Gfi1 is primarily important in myeloid and lymphoid differentiation, whereas Gfi1b is crucial for the generation of red blood cells and platelets. Several rare hematologic diseases are associated with acquired or inheritable mutations in the GFI1 and GFI1B genes. Certain patients with severe congenital neutropenia carry mutations in the GFI1 gene that lead to the disruption of the C-terminal zinc finger domains. Other mutations have been found in the GFI1B gene in families with inherited bleeding disorders. In addition, the Gfi1 locus is frequently found to be a proviral integration site in retrovirus-induced lymphomagenesis, and new, emerging data suggest a role of Gfi1 in human leukemia and lymphoma, underlining the role of both factors not only in normal hematopoiesis, but also in a wide spectrum of human blood diseases.

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Figures

Figure 1
Figure 1
Structure and function of Gfi1 and Gfi1b. (A) Schematic structure of Gfi1 and Gfi1b with their respective domains. (B) Depiction of the different Gfi1 interaction partners and their ability to modify histones at Gfi1 target gene loci.
Figure 2
Figure 2
Hierarchical structure of hematopoiesis depicting the stepwise differentiation from hematopoietic stem and precursor cells into effector cells of the main lineages. Shaded fields indicate Gfi1 and Gfi1b expression levels. CLP, common lymphoid progenitor; ETP, early thymic progenitor; GMP, granulocyte-monocyte progenitor; LMPP, lymphoid primed multipotent progenitor; MEP, megakaryocyte-erythroid progenitor; MPP, multipotent progenitor.
Figure 3
Figure 3
Effect of mutations on the structure of GFI1. (A) Schematic structure of zing fingers 5 and 6 of Gfi1 and localization of the most common mutations found in families with SCN. The affected amino acids are indicated. (B) Consequence of the N382S mutation on the tertiary structure of zinc finger 5 in the human GFI1 protein: in the wild-type form, Asn-382 forms 2 hydrogen bonds with the DNA strand, which is lost in the GFI1 variant carrying the N382S mutation (red circle).
Figure 4
Figure 4
Effect of mutations on the structure of GFI1b. (A) Schematic structure of zinc finger 5 of Gfi1b and localization of the 2 mutations (Q287* and H294fs) found in families with inherited “bleeding disorder platelet-type, 17” (BDPLT17; OMIM 187900) or “Gfi1b-related thrombocytopenia” (GFI1B-RT). (B) The missense Q287* mutation introduces a premature stop codon in GFI1B causing a truncation and loss of the α helix strand in the third zinc finger domain in GFI1b (arrow).
Figure 5
Figure 5
Positions of known mutations in the genes for GFI1 and GFI1B. Shown is a summary of the consequences of the known inherited and congenital mutations in the human GFIB gene (upper) and the human GFI1 gene (lower) for their respective protein sequences. All mutations in the GFI1B gene are associated with platelet disorders, and the mutations in the GFI1 gene are associated with SCN.
Figure 6
Figure 6
Summary of hematologic diseases associated with perturbed expression or mutations of GFI1 or GFI1B.
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