Myeloproliferative disease induced by TEL-PDGFRB displays dynamic range sensitivity to Stat5 gene dosage

Jennifer A. Cain, Zhifu Xiang, Julie O'Neal, Friederike Kreisel, Annalynn Colson, Hui Luo, Lothar Hennighausen, Michael H. Tomasson

Research output: Contribution to journalArticlepeer-review

41 Scopus citations


Expression of the constitutively activated TEL/PDGFβR fusion protein is associated with the t(5;12)(q33;p13) chromosomal translocation found in a subset of patientswith chronic myelomonocytic leukemia. TEL/PDGFβR 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 TELPDGFRB 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 TPiGFP→Stat5a-/- 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 TPiGFP→Stat5b-/- 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.

Original languageEnglish
Pages (from-to)3906-3914
Number of pages9
Issue number9
StatePublished - May 1 2007


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