Abstract
Emergency granulopoiesis occurs in response to infectious or inflammatory challenge and is a component of the innate immune response. Some molecular events involved in initiating emergency granulopoiesis are known, but termination of this process is less well defined. In this study, we found that the interferon consensus sequence binding protein (Icsbp/Irf8) was required to terminate emergency granulopoiesis. Icsbp is an interferon regulatory transcription factor with leukemia suppressor activity. Expression of Icsbp is decreased in chronic myeloid leukemia, and Icsbp(-/-) mice exhibit progressive granulocytosis with evolution to blast crisis, similar to the course of human chronic myeloid leukemia. In this study, we found aberrantly sustained granulocyte production in Icsbp(-/-) mice after stimulation of an emergency granulopoiesis response. Icsbp represses transcription of the genes encoding Fas-associated phosphatase 1 (Fap1) and growth arrest-specific 2 (Gas2) and activates genes encoding Fanconi C and F. After stimulation of emergency granulopoiesis, we found increased and sustained expression of Fap1 and Gas2 in bone marrow myeloid progenitor cells from Icsbp(-/-) mice in comparison with the wild type. This was associated with resistance to Fas-induced apoptosis and increased β-catenin activity in these cells. We also found that repeated episodes of emergency granulopoiesis accelerated progression to acute myeloid leukemia in Icsbp(-/-) mice. This was associated with impaired Fanconi C and F expression and increased sensitivity to DNA damage in bone marrow myeloid progenitors. Our results suggest that impaired Icsbp expression enhances leukemogenesis by deregulating processes that normally limit granulocyte expansion during the innate immune response.
Highlights
Steady-state granulopoiesis is a continuous homeostatic process for replacing granulocytes that are lost to normal programmed cell death
We found that impaired expression of growth arrest-specific 2 (Gas2) and Fas-associated phosphatase 1 (Fap1) contributes to the leukemia suppression effect of Icsbp
IcsbpϪ/Ϫ Mice Exhibited a Sustained Emergency Granulopoiesis Response—In a low-pathogen environment, young IcsbpϪ/Ϫ mice exhibit mild granulocytosis that increases with age
Summary
The first identified Icsbp target genes encoded proteins involved in the effector functions of granulocytes, monocytes, or both (e.g. NADPH oxidase proteins, Toll-like receptors, lysosome-related genes, and MHC class I proteins) [13, 15, 16, 27, 28]. We found stabilization of -catenin protein in Bcr-ablϩ or IcsbpϪ/Ϫ bone marrow progenitors in a Gas2/calpain-dependent manner, increasing proliferation (via cyclin D1 and c-myc), and decreasing apoptosis (via survivin) [22]. The effects of Fap were inhibited by a Fas-C-terminal tripeptide that blocks a Fap protein/protein interaction domain (SLV peptide) [21, 23, 35] These prior studies have implicated Fap and Gas in leukemogenesis, the role of these proteins in normal granulopoiesis was unknown. We found that Icsbp contributes to the termination of emergency granulopoiesis by repressing genes encoding Fap and Gas2 This antagonizes mechanisms of progenitor expansion that are stimulated during emergency granulopoiesis (i.e. Fas resistance and -catenin activation). This connection is implied by the observed increase in C/EBP-expression in human CML and the association of Stat activation with AML in severe congenital neutropenia [36, 37]
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