Blood, 15 October 2002, Vol. 100, No. 8, pp. 2685-2686
Gfi-1B and erythroid development
The paradigm of transcriptional regulation of differentiation
has been demonstrated with considerable veracity in the hematopoietic system, and Osawa and colleagues (page 2769) add a novel
player to the growing list of significant transcription factors.
We first learned about the Gfi family of transcription factors through
the identification of Gfi-1 as an integration site of the Moloney
murine leukemia virus. Gfi-1 was also shown to participate with c-myc
and pim-1 in lymphoma formation in Eµ/myc and Eµ-pim1 transgenic
mice, respectively. Gfi-1B was identified by its sequence similarity to
Gfi-1, and both proteins display identical domain architecture
with 1 SNAG and 6 zinc finger domains.
Osawa and colleagues became interested in Gfi-1B due
to its high expression in hematopoietic stem cells. Overexpression of Gfi-1B in CD34+ cells resulted in the formation
of EPO-independent erythroblast formation in clonogenic assays, as well
as strong induction of Glycophorin A-positive cells in liquid culture.
Gfi-1B did not affect mitogenesis in proliferation assays.
Structure-function experiments revealed that the zinc finger
domains of Gfi-1B are required for formation of Glycophorin A-positive
cells. Enforced expression of Gfi-1B resulted in the
expression of GATA-2, with no effect on SCL and
GATA-1.
In parallel studies, the Orkin laboratory has shown that
targeting Gfi-1B results in embryonic lethality due to a profound defect in formation of enucleated erythrocytes (Saleque et al, Genes Dev. 2002;16:301-306). Both erythroid and megakaryocyte development is arrested in Gfi-1B null animals.
Several important issues regarding Gfi-1B remain to be resolved.
Evidence is presented within the Osawa study that Gfi-1B can serve as
both an activator or a repressor of transcription, depending on the
promoter and cell type under study. This report also suggests that
Gfi-1B may regulate GATA-2 expression, but this could be due
to an accumulation of erythroid cells in their assay.
Gfi-1 binds to the SUMO ligase PIAS3, suggesting a role in
negative regulation. Clearly, identification of additional Gfi-1/1B
targets, identification of potential synergy between Gfi-1/1B and the
panoply of hematopoietic transcription factors, and
characterization of significant Gfi-1/1B binding interactions will tell
us more about the interplay of this interesting family of transcription factors.
Dwayne L. Barber
Ontario Cancer Institute
