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Blood, 1 May 2007, Vol. 109, No. 9, pp. 3906-3914.
Prepublished online as a Blood First Edition Paper on January 11, 2007; DOI 10.1182/blood-2006-07-036335.
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Submitted July 19, 2006
Accepted December 26, 2006
Myeloproliferative disease induced by TEL-PDGFRB
displays dynamic range sensitivity to Stat5a gene
dosage
Jennifer A. Cain, Zhifu Xiang, Julie O'Neal, Friederike Kreisel, AnnaLynn Colson, Hui Luo, Lothar Hennighausen, and Michael H. Tomasson*
Dept of Internal Medicine, Division of Oncology, Washington University School of Medicine, Siteman Cancer Center, St. Louis, MO, United States
Dept of Pathology, Washington University School of Medicine, St. Louis, MO, United States
Laboratory of Genetics & Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States
* Corresponding author; email: tomasson{at}im.wustl.edu.
Expression of the constitutively activated TEL/PDGF R fusion protein is associated with the t(5;12)(q33;p13) chromosomal translocation found in a subset of patients with chronic myelomonocytic leukemia. TEL/PDGFR activates multiple signal transduction pathways in cell culture systems and expression of the TEL-PDGFRB fusion gene induces myeloproliferative disease (MPD) in mice. We used gene-targeted mice to characterize the contribution of signal transducer and activator of transcription (Stat) and Src family genes to TEL-PDGFRB-mediated transformation in methylcellulose colony and murine bone marrow transduction/transplantation assays. Fetal liver hematopoietic stem and progenitor cells harboring targeted deletion of both Stat5a and Stat5b (Stat5abnull/null) genes were refractory to transformation by TEL-PDGFRB in methylcellulose colony assays. Notably, these cell populations were maintained in Stat5abnull/null fetal livers and succumbed to transformation by c-Myc. Surprisingly, targeted disruption of either Stat5a or Stat5b alone also impaired TEL-PDGFRB-mediated transformation. Survival of TPiGFP Stat5a-/- and TPiGFPStat5a+/- transplanted mice was significantly prolonged, demonstrating significant sensitivity of TEL-PDGFRB-induced MPD to the dosage of Stat5a. TEL-PDGFRB mediated MPD was incompletely penetrant in TPiGFPStat5b-/- mice. In contrast, Src family kinases Lyn, Hck, and Fgr and the Stat family member Stat1 were dispensable for TEL-PDGFRB disease. Together, these data demonstrate that Stat5a and Stat5b are dose-limiting mediators of TEL-PDGFRB-induced myeloproliferation.
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