STAT3 controls myeloid progenitor growth during emergency granulopoiesis

H Zhang, H Nguyen-Jackson… - Blood, The Journal …, 2010 - ashpublications.org
H Zhang, H Nguyen-Jackson, AD Panopoulos, HS Li, PJ Murray, SS Watowich
Blood, The Journal of the American Society of Hematology, 2010ashpublications.org
Granulocyte colony-stimulating factor (G-CSF) mediates “emergency” granulopoiesis during
infection, a process that is mimicked by clinical G-CSF use, yet we understand little about the
intracellular signaling cascades that control demand-driven neutrophil production. Using a
murine model with conditional deletion of signal transducer and activator of transcription 3
(STAT3) in bone marrow, we investigated the cellular and molecular mechanisms of STAT3
function in the emergency granulopoiesis response to G-CSF administration or infection with …
Abstract
Granulocyte colony-stimulating factor (G-CSF) mediates “emergency” granulopoiesis during infection, a process that is mimicked by clinical G-CSF use, yet we understand little about the intracellular signaling cascades that control demand-driven neutrophil production. Using a murine model with conditional deletion of signal transducer and activator of transcription 3 (STAT3) in bone marrow, we investigated the cellular and molecular mechanisms of STAT3 function in the emergency granulopoiesis response to G-CSF administration or infection with Listeria monocytogenes, a pathogen that is restrained by G-CSF signaling in vivo. Our results show that STAT3 deficiency renders hematopoietic progenitor cells and myeloid precursors refractory to the growth-promoting functions of G-CSF or L monocytogenes infection. STAT3 is necessary for accelerating granulocyte cell-cycle progression and maturation in response to G-CSF. STAT3 directly controls G-CSF–dependent expression of CCAAT-enhancer-binding protein β (C/EBPβ), a crucial factor in the emergency granulopoiesis response. Moreover, STAT3 and C/EBPβ coregulate c-Myc through interactions with the c-myc promoter that control the duration of C/EBPα occupancy during demand-driven granulopoiesis. These results place STAT3 as an essential mediator of emergency granulopoiesis by its regulation of transcription factors that direct G-CSF–responsive myeloid progenitor expansion.
ashpublications.org