Myeloproliferative disease induced by TEL-PDGFRB displays dynamic range sensitivity to Stat5 gene dosage.
Expression of the constitutively activated TEL/PDGFbetaR fusion protein is associated with the t(5;12)(q33;p13) chromosomal translocation found in a subset of patients with chronic myelomonocytic leukemia. TEL/PDGFbetaR 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 (Stat5ab(null/null)) genes were refractory to transformation by TEL-PDGFRB 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 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.
Cain
Jennifer A
JA
Department of Internal Medicine, Division of Oncology, Washington University Siteman Cancer Center, 550 S. Euclid Avenue, St. Louis, MO 63110, USA.
Xiang
Zhifu
Z
O'Neal
Julie
J
Kreisel
Friederike
F
Colson
AnnaLynn
A
Luo
Hui
H
Hennighausen
Lothar
L
Tomasson
Michael H
MH
D000818:Animals; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D018628:Gene Dosage; D015973:Gene Expression Regulation, Leukemic / Q000235:genetics; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D015514:Oncogene Proteins, Fusion / Q000096:biosynthesis* / Q000235:genetics; D050783:Proto-Oncogene Proteins c-ets / Q000096:biosynthesis* / Q000235:genetics; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000096:biosynthesis* / Q000235:genetics; D012097:Repressor Proteins / Q000096:biosynthesis* / Q000235:genetics; D050799:STAT5 Transcription Factor / Q000096:biosynthesis* / Q000172:deficiency; D015398:Signal Transduction / Q000235:genetics; D014178:Translocation, Genetic / Q000235:genetics; D014410:Tumor Stem Cell Assay; D019061:src-Family Kinases / Q000378:metabolism; D000097764:ETS Translocation Variant 6 Protein
D015514:Oncogene Proteins, Fusion; D050783:Proto-Oncogene Proteins c-ets; D020797:Receptor, Platelet-Derived Growth Factor beta; D012097:Repressor Proteins; D050799:STAT5 Transcription Factor; D019061:src-Family Kinases; D000097764:ETS Translocation Variant 6 Protein; C494093:Stat5a protein, mouse; C494096:Stat5b protein, mouse