ICSBP Directs Bipotential Myeloid Progenitor Cells to Differentiate into Mature Macrophages

Abstract

During hematopoiesis, myeloid progenitor cells give rise to granulocytes and macrophages. To study the role for ICSBP, a hematopoietic cell-specific transcription factor in myeloid cell development, the gene was introduced into myeloid progenitor cells established from ICSBP-/- mice. ICSBP retrovirus-transduced cells differentiated into mature macrophages with phagocytic activity, which coincided with the induction of specific target DNA binding activity. Similar to macrophages in vivo, ICSBP-transduced cells were growth arrested, expressed many macrophage-specific genes, and responded to macrophage activation signals. Contrary to this, ICSBP transducion led to repression of granulocyte-specific genes and inhibited G-CSF-mediated granulocytic differentiation in these and other myeloid progenitor cells. Together, ICSBP has a key role in the myeloid cell lineage selection and macrophage maturation.

Interferon Regulatory Factor-8 Is Indispensable for the Expression of Promyelocytic Leukemia and the Formation of Nuclear Bodies in Myeloid Cells

“…IRF-8 Ϫ/Ϫ mice harbor an increased number of myeloid progenitor cells defective in the ability to differentiate to macrophages and consequently mature mainly to granulocytes. Accordingly, these IRF-8-deficient mice eventually develop a CML-like disease (6,12). In humans, 66% of AML and 79% of CML patients exhibit reduced levels of IRF-8 or no expression at all.…”

“…CL-2 murine macrophage cell line and Tot2 myeloid progenitor cell line were derived from IRF-8 Ϫ/Ϫ mice and maintained as described previously (6,28).…”

“…This factor is expressed exclusively in immune cells and accordingly plays a major role in the differentiation, development, and function of macrophages (4 -6), dendritic cells (7)(8)(9)(10), and B-cells (11). Mice with IRF-8 null mutation are defective in the ability of myeloid progenitor cells to mature toward macrophage lineage and eventually develop chronic myelogenous leukemia (CML)-like syndrome (6,12). Furthermore, IRF-8 blocks the development of murine Bcr-Ablinduced CML (13) through the inhibition of Bcl-2 (14) and induction of anti-leukemic immunity (15).…”

Long-Term Suppression of Tumor Growth by TNF Requires a Stat1- and IFN Regulatory Factor 1-Dependent IFN-γ Pathway but Not IL-12 or IL-18

“…A transcription factor that may be critical for determining the macrophage phenotype is IFN consensus sequence binding protein (ICSBP), an IFN-␥-inducible transcription factor specifically expressed in hemopoietic cells. ICSBP is required for the differentiation of myeloid progenitors into mature macrophages (41) and, in combination with IRF-1 and PU.1, regulates a number of IFN-␥-responsive genes. It is tempting to speculate that ICSBP may direct mature macrophages to differentiate further into a cell type that is required for TNF to suppress tumor growth.…”

Identification of IRF-8 and IRF-1 target genes in activated macrophages

“…Consistent with this, lack of IRF-8 was reported in human myeloid leukemias, implicating its pivotal role as a tumor suppressor gene (Schmidt et al 1998). Thus, IRF-8 drives bipotential myeloid progenitor cells towards mature macrophages while inhibiting the differentiation pathway towards granulocytes (Tamura et al 2000). In addition, it was shown that IRF-8 is an essential factor for proper functioning of mature macrophages.…”