The mechanism of granulopoiesis and leukemogenesis by the activation of Stat3

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The Jak-Stat pathway plays an essential role in cytokine signaling. G-CSF promotes granulopoiesis, and Stat3 is the principle Stat protein activated by G-CSF. Upon treatment with G-CSF, the IL-3 dependent cell line 32D clone 3(32Dcl3) differentiates into neutrophils, and 32Dcl3 cells expressing dominant-negative Stat3 (32Dcl3/DNStat3) proliferate in G-CSF without differentiation. Gene expression profile of G-CSF-stimulated cell lines revealed that the expression of C/EBP_α was up-regulated by the activation of Stat3. And activated Stat3 bound to C/EBP_α, leading to the enhancement of the transcription activity of C/EBP_α. Conditional expression of C/EBP_α in 32Dcl3/DNStat3 cells after G-CSF stimulation abolishes the G-CSF dependent cell proliferation and induces granulocytic differentiation. These results show that one of the major roles of Stat3 in G-CSF signaling pathway is to augment the function of C/EBP_α.The function of Stat3 in vivo was examined using the Stat3 conditional deficient mice. Mice deficient for Stat3 in hematopoietic cells show neutrocytosis, and G-CSF-induced proliferation of progenitor cells was observed in Stat3-deficient mice. In hematopoietic cells from Stat3-deficient mice, trace levels of SOCS3, a negative regulator of granulopoiesis, were observed, and SOCS3 expression was not induced by G-CSF stimulation. Stat3 null bone marrow cells displayed a significant activation of ERK1/2 under basal conditions, and it was enhanced and sustained by G-CSF stimulation. Furthermore, the augmented proliferation of Stat3-deficient bone marrow cells in response to G-CSF was dramatically decreased by addition of a MEK1 inhibitor. Stat3 functions in vivo as a negative regulator of G-CSF signaling by inducing SOCS3 expression, and ERK activation is the major factor responsible for inducing the proliferation of hematopoietic cells in response to G-CSF.