Journal article
Myeloproliferative disease induced by TEL-PDGFRB displays dynamic range sensitivity to Stat5 gene dosage
Blood, Vol.109(9), pp.3906-3914
Neoplasia
05/01/2007
DOI: 10.1182/blood-2006-07-036335
PMCID: PMC1874559
PMID: 17218386
Abstract
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 patients with 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 (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
TP
i
GFP
→
Stat5a
−/−
and
TP
i
GFP
→
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
TP
i
GFP
→
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.
Details
- Title: Subtitle
- Myeloproliferative disease induced by TEL-PDGFRB displays dynamic range sensitivity to Stat5 gene dosage
- Creators
- Jennifer A Cain - Department of Internal Medicine, Division of Oncology, Washington University, Siteman Cancer Center, St Louis, MOZhifu Xiang - Department of Internal Medicine, Division of Oncology, Washington University, Siteman Cancer Center, St Louis, MOJulie O'Neal - Department of Internal Medicine, Division of Oncology, Washington University, Siteman Cancer Center, St Louis, MOFriederike Kreisel - Department of Pathology, Washington University School of Medicine, St Louis, MOAnnaLynn Colson - Department of Internal Medicine, Division of Oncology, Washington University, Siteman Cancer Center, St Louis, MOHui Luo - Department of Internal Medicine, Division of Oncology, Washington University, Siteman Cancer Center, St Louis, MOLothar Hennighausen - Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MDMichael H Tomasson - Department of Internal Medicine, Division of Oncology, Washington University, Siteman Cancer Center, St Louis, MO
- Resource Type
- Journal article
- Publication Details
- Blood, Vol.109(9), pp.3906-3914
- Publisher
- American Society of Hematology
- Series
- Neoplasia
- DOI
- 10.1182/blood-2006-07-036335
- PMID
- 17218386
- PMCID
- PMC1874559
- ISSN
- 0006-4971
- eISSN
- 1528-0020
- Language
- English
- Date published
- 05/01/2007
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984094539502771
Metrics
14 Record Views