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

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.

Original Research: A case-control genome-wide association study identifies genetic modifiers of fetal hemoglobin in sickle cell disease

“…GFi1 and its paralog GFi1B are critical transcriptional regulators for proliferation and maturation of hematopoietic stem cells. [48][49][50] Although it is unclear whether GFi1/GFi1B plays a role in repressing g-globin transcription, our analysis provides evidence for a potential GFi1 regulatory sequence in the HbF silencing region.…”

“…The formation of protein complexes between GFi1/GFi1B mediates histone modifications associated with gene transcription silencing and regulation of hematopoiesis. [48][49][50]81 Studies by Vassen and colleagues demonstrated increased transcription of the embryonic and fetal globin genes and delayed erythroid maturation in Gfi1B-null mice 82 providing evidence that GFi1/GFi1B are involved in murine globin gene regulation.…”

Should any genetic defect affecting α‐granules in platelets be classified as gray platelet syndrome?

“…GFI1B is a proto-oncogene and transcriptional regulator that with its paralog, GFI1, acts as a gene repressor during early hematopoietic stem cell development [22][23][24][25]. GFI1 primarily intervenes in myeloid and lymphoid generation and genetic variants cause neutropenia.…”

“…We show the full-length GFI1B protein, a shorter splice form lacking ZNF2 and parts of ZNF1 and 3 may also be found in hematopoietic tissue. The mutations or non-synonymous SNPs identified by Chen et al [25] are in black and occur along the protein; the truncating mutations within exon 6 characterized by Stevenson et al [27] and by Monteferrario et al [28] and affecting ZNF5 and 6 are in red. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]…”

Atoh1 in sensory hair cell development: constraints and cofactors

“…Here it controls diverse developmental processes, such as cell fate determination, differentiation, proliferation and cell survival (for review, see (50)(51)(52)(53)(54)). Outside the hematopoietic system, Gfi1 mRNA has been detected in a wide range of other tissues, but expression of Gfi1 protein seems to be restricted to mechanoreceptors cells (hair cells and Merkel cells), neurons of the cerebellum and retina, and specialized epithelial cells in the gut and lung (Table 1).…”