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Published online before print July 18, 2007

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.1206766

Received for publication December 27, 2006.
Revised June 13, 2007.
Accepted for publication June 18, 2007.

Article

Conditional overexpression of Stat3 in differentiating myeloid cells results in neutrophil expansion and induces a distinct, antiapoptotic and pro-oncogenic gene expression pattern

Michele S. Redell ^*, Anna Tsimelzon , Susan G. Hilsenbeck , and David J. Tweardy ^@

Departments of *Pediatrics, Section of Hematology-Oncology, and Medicine, Section of Infectious Diseases, and Breast Center Biostatistics and Informatics Core, Baylor College of Medicine, Houston, Texas, USA

^@ To whom correspondence should be addressed. E-mail: dtweardy{at}bcm.tmc.edu.

	Abstract

Normal neutrophil development requires G-CSF signaling, which includes activation of STAT3. Studies of G-CSF-mediated Stat3 signaling in cell culture and transgenic mice have yielded conflicting data regarding the role of Stat3 in myelopoiesis. The specific functions of Stat3 remain unclear, in part, because two isoforms, Stat3 and Stat3, are expressed in myeloid cells. To understand the contribution of each Stat3 isoform to myelopoiesis, we conditionally overexpressed Stat3 or Stat3 in the murine myeloid cell line 32Dcl3 (32D) and examined the consequences of overexpression on cell survival and differentiation. 32D cells induced to overexpress Stat3, but not Stat3, generated a markedly higher number of neutrophils in response to G-CSF. This effect was a result of decreased apoptosis but not of increased proliferation. Comparison of gene expression profiles of G-CSF-stimulated, Stat3-overexpressing 32D cells with those of cells with normal Stat3 expression revealed novel Stat3 gene targets, which may contribute to neutrophil expansion and improved survival, most notably Slc28a2, a purine nucleoside transporter, which is critical for maintenance of intracellular nucleotide levels and prevention of apoptosis, and Gpr65, an acid-sensing, G protein-coupled receptor with pro-oncogenic and antiapoptotic functions.

Key Words: transcription factor • apoptosis • hematopoiesis

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