Gfi1 integrates progenitor versus granulocytic transcriptional programming

Abstract

In patients with severe congenital neutropenia (SCN) and mice with growth factor independent-1 (Gfi1) loss of function, arrested myeloid progenitors accumulate, whereas terminal granulopoiesis is blocked. One might assume that Gfi-null progenitors accumulate because they lack the ability to differentiate. Instead, our data indicate that Gfi1 loss of function deregulates 2 separable transcriptional programs, one of which controls the accumulation and lineage specification of myeloid progenitors, but not terminal granulopoiesis. We demonstrate that Gfi1 directly represses HoxA9, Pbx1, and Meis1 during normal myelopoiesis.

Lysine-specific demethylase 1 restricts hematopoietic progenitor proliferation and is essential for terminal differentiation

“…11 Consistent with these in vitro findings, we observed more than a 4-fold de-repression of Gfi1b in dox-treated shLSD1 mice (Figure 2i). Gfi1 restricts progenitor expansion via HoxA9 and Meis1 gene repression, 28 which is likely mediated by LSD1 since LSD1-kd upregulated HoxA9 and Meis1 (Figure 2i). The downregulation of CXCR4 (Figure 2i) that we observed could explain the diminished bone marrow retention of LSD1-kd progenitors and HSCs.…”

Gfi-1 inhibits proliferation and colony formation of p210BCR/ABL-expressing cells via transcriptional repression of STAT 5 and Mcl-1

“…Among the genes whose expression was downregulated upon Gfi-1 activation, STAT 5B and Mcl-1 attracted our attention because of their involvement in proliferation and survival of hematopoietic stem cells. 25 --28 In a recent study investigating the role of Gfi-1 in normal hematopoiesis, 37 Gfi-1 knockout mice showed an expansion of early myeloid progenitors associated with increased expression of HoxA9, Pbx1 and Meis1, which appear to be direct targets of Gfi-1. However, expression of HoxA9 is low in K562 cells and activation of Gfi-1 did not induce a decrease in HoxA9 levels, suggesting that Gfi-1 exerts its effects through multiple downstream effectors.…”

Gfi1 and Gfi1b: key regulators of hematopoiesis

“…47,48,55 Inhibitor of DNA binding 2 (Id2) is a Gfi1 target gene and Id2 expression is elevated in myeloid progenitors from Gfi1-null mice. 56 Reducing Id2 levels in a Gfi1-null background partially restored the expansion of immature myeloid cells.…”

“…This indicates that the expansion of the immature myeloid population in Gfi1-null mice also depends on HoxA9 induction. 55 Indeed, Gfi1 directly represses HoxA9 gene expression and this repression is lost in cells lacking functional Gfi1 (Table 1). In line with the finding that HoxA9 overexpression triggers myeloid malignancies in mice, 57,58 Gfi1-null mice show features that are reminiscent of acute myeloid leukemia.…”