Severe congenital neutropenia (SCN) is an inborn disorder of granulopoiesis. Mutations of the ELA2 gene encoding neutrophil elastase (NE) are responsible for most cases of SCN and cyclic neutropenia (CN), a related but milder disorder of granulopoiesis. However, the mechanisms by which these mutations disrupt granulopoiesis are unclear. We hypothesize that the ELA2 mutations result in the produ...

Normally, neutrophil pools are maintained by homeostatic mechanisms that require the transcription factor C/EBPα. Inflammation, however, induces neutrophilia through a distinct pathway of "emergency" granulopoiesis that is dependent on C/EBPβ. Here, we show in mice that alum triggers emergency granulopoiesis through the IL-1RI-dependent induction of G-CSF. G-CSF/G-CSF-R neutralization impairs p...

We investigated the in vivo effects of erythropoietin (EPO) on granulopoiesis and, conversely, the effect of granulocyte colony-stimulating factor (G-CSF) treatment on erythropoiesis. Recombinant human EPO at four different doses in combination with recombinant human G-CSF also at four different doses was simultaneously administered for 7 days to splenectomized mice. In total, 16 different comb...

Granulocyte colony-stimulating factor (G-CSF) is the principal cytokine regulating granulopoiesis. Truncation mutations of the G-CSF receptor (G-CSFR) are associated with the development of acute myeloid leukemia in patients with severe congenital neutropenia. Although increased proliferative signaling by a representative G-CSFR truncation mutation (termed d715) has been documented, the molecul...

The present studies were performed to determine whether the sensitivity of a normal human granulopoiesis to Adriamycin changes after repeated exposure to the drug in vivo. A single-layer agar culture for the in vitro growth of granulocytic colonies from committed stem cells was used as the assay system. The in vitro sensitivity of the human granulopoiesis to different doses of Adriamycin was de...

In addition to classic homeostatic granulocyte production mediated by G-CSF and GM-CSF, an independent pathway stimulated by IL6 complexed with its soluble receptor (sIL6R) contributes to emergency granulopoiesis.

Steady-state hematopoiesis responds to extracellular stimuli to meet changing demands and also to pathologically altered intracellular signaling. Granulocyte production increases following infection or in response to cytokine stimulation, and activation of the CCAAT/enhancer-binding protein β (C/EBPβ) transcription factor is required for such stress-induced granulopoiesis, whereas C/EBPα plays ...

A transplantable granulocytosis-inducing mammary adenocarcinoma of mice was used to provide evidence about the role of tumor-generated factors in granulopoiesis. The original tumor produced high levels of colony-stimulating factor (CSF) in culture as well as inhibitor to CSF. The tumor was passaged repeatedly, both in host mice and in culture, and eventually displayed a varying capacity to indu...

The Lamin B receptor (LBR) is a pivotal architectural protein in the nuclear envelope. Mutations in the Lamin B receptor lead to nuclear hyposegmentation (Pelger-Huët anomaly). We have exactly quantified the nuclear lobulation in neutrophils from individuals with 0, 1, 2 and 3 functional copies of the lamin B receptor gene and analyzed the effect of different mutation types. Our data demonstrat...

Provision of colony-stimulating activity (CSA) by human marrow cells was determined utilizing culture techniques in vitro to assess intramedullary cellular interactions on human granulopoiesis. CSA production from marrow cells of 21 patients with acute myeloid leukemia (AML) was evaluated and compared to normal marrow by testing the capacity of conditioned media from adherent marrow cells to pr...