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

被引:39
作者
Cain, Jennifer A.
Xiang, Zhifu
O'Neal, Julie
Kreisel, Friederike
Colson, AnnaLynn
Luo, Hui
Hennighausen, Lothar
Tomasson, Michael H.
机构
[1] Washington Univ, Siteman Canc Ctr, Dept Internal Med, Div Oncol, St Louis, MO USA
[2] Washington Univ, Sch Med, Dept Pathol, St Louis, MO USA
[3] NIDDK, Lab Genet & Physiol, NIH, Bethesda, MD USA
关键词
D O I
10.1182/blood-2006-07-036335
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Expression of the constitutively activated TEL/PDGF beta R fusion protein is associated with the t(5;12)(q33;pl3) chromosomal translocation found in a subset of patients with chronic myelomonocytic leukemia. TEL/PDGF beta R 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 (Staffab(null/null)) genes were refractory to transformation by TELPDGFRB in methylcellulose colony assays. Notably, these cell populations were maintained in Stat5ab(null/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 TFIGFP -> 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 TFIGFP -> 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.
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页码:3906 / 3914
页数:9
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