Comment on Zeng et al, page 167
In this issue of Blood, Zeng and colleagues report on the interferon-γ (IFN-γ)-inducible patterns of gene expression in normal bone marrow-derived CD34 cells. A comparison with patterns of constitutive gene expression seen in CD34 cells from aplastic bone marrows demonstrates many similarities, further implicating IFN-γ in the pathophysiology of bone marrow failure.
Acquired aplastic anemia is a clinical entity characterized by pancytopenia and an empty bone marrow.1 The pathophysiology of this disease has been the subject of extensive investigations in the past 2 decades It is now widely accepted that the bone marrow suppression seen in idiopathic aplastic anemia results from an immune mechanism that involves overproduction of myelosuppressive cytokines, including interferon-γ (IFN-γ) and tumor necrosis factor (TNF).2
There is extensive evidence that IFN-γ plays a key role in the immune pathophysiology of aplastic anemia.1,2 After the original observations implicating overproduction of IFN-γ by abnormally activated T cells in the pathogenesis of the disease,3,4 a large body of work has confirmed the relevance of excessive IFN-γ in the development of bone marrow failure.1,2 Our overall understanding of the immune mechanisms mediating hematopoietic suppression has also evolved substantially over the years.1,2 Such advances have increased the potential for developing novel targeted therapeutic approaches for aplastic anemia and may have various other practical clinical implications. For instance, recent studies have established that intracellular IFN-γ levels in circulating and marrow T cells may be predictive of response to immunosuppressive therapy, as well as the onset of relapse in aplastic patients,5 suggesting that in the future intracellular IFN-γ levels may be used to predict response to treatment or to monitor for possible relapse.
IFN-γ is the only known type II IFN and, like all other IFNs, it exhibits potent antiviral and growth-inhibitory effects in a variety of target cells. A major mechanism by which this cytokine mediates functional responses is the activation of Jak-Stat signaling pathways in target cells, resulting in the transcriptional activation of multiple target genes.6 Despite the advances in the research area of transcriptional regulation by IFNs, much remains to be learned on the functional roles of the many interferon-regulated genes and their roles in the induction of distinct responses. The identities of genes and gene products that may be involved in the regulation of antiproliferative versus antiviral effects, or gene products that may participate in the generation of IFN-induced responses under normal conditions, or in pathophysiogic states, remain to be clarified.
In the current issue of Blood, Zeng and colleagues used microarray analysis of RNA expression profiles to examine the patterns of gene expression seen in normal bone marrow-derived CD34+ cells, or stromal cells, after treatment with IFN-γ in vitro. They also compared such patterns of interferon-induced gene expression to the interferon-regulated genes that are constitutively expressed in aplastic anemia and/or paroxysmal nocturnal hemoglobinuria (PNH)-derived CD34 progenitors. Their data indicate that several of the genes expressed in normal CD34+ cells in response to IFN-γ are also overexpressed in CD34+ cells derived from aplastic anemia bone marrows. Among those are genes involved in the regulation of apoptosis, such as FAS and TRAIL; genes encoding for cytokines or chemokines, such as TNF and CCL5; genes encoding for proteins that regulate cell adhesion, such as endothelial growth factor 1 or vascular cell adhesion molecule 1; and transcription factor genes, such as STAT1. These data firmly establish a specific pattern of gene induction in response to interferon in progenitor cells, and suggest that the similar pattern seen in aplastic anemia bone marrows reflects a “molecular stamp” of exposure to IFN-γ in vivo. Altogether, these findings further implicate IFN-γ in the pathogenesis of bone marrow failure in humans and form the basis for future work to identify the precise contribution of different IFN-inducible genes in mediating the myelosuppressive effects of IFNs. Such future work is very important, as it may lead to the identification of genes and protein products that could be used as molecular targets for the design of novel drugs for the treatment of aplastic anemia and other bone marrow failure syndromes. ▪
