Journal article
Fatal myeloproliferation, induced in mice by TEL/PDGFβR expression, depends on PDGFβR tyrosines 579/581
The Journal of clinical investigation, Vol.105(4), pp.423-432
02/15/2000
DOI: 10.1172/JCI8902
PMCID: PMC289168
PMID: 10683371
Abstract
The t(5;12)(q33;p13) translocation associated with chronic myelomonocytic leukemia (CMML) generates a
TEL/PDGFβR
fusion gene. Here, we used a murine bone marrow transplant (BMT) assay to test the transforming properties of TEL/PDGFβR in vivo. TEL/PDGFβR, introduced into whole bone marrow by retroviral transduction, caused a rapidly fatal myeloproliferative disease that closely recapitulated human CMML. TEL/PDGFβR transplanted mice developed leukocytosis with Gr-1
+
granulocytes, splenomegaly, evidence of extramedullary hematopoiesis, and bone marrow fibrosis, but no lymphoproliferative disease. We assayed mutant forms of the TEL/PDGFβR fusion protein — including 8 tyrosine to phenylalanine substitutions at phosphorylated PDGFβR sites to which various SH2 domain–containing signaling intermediates bind — for ability to transform hematopoietic cells. All of the phenylalanine (F-) mutants tested conferred IL-3-independence to a cultured murine hematopoietic cell line, but, in the BMT assay, different F-mutants displayed distinct transforming properties. In transplanted animals, tyrosines 579/581 proved critical for the development of myeloproliferative phenotype. F-mutants with these residues mutated showed no sign of myeloproliferation but instead developed T-cell lymphomas. In summary, TEL/PDGFβR is necessary and sufficient to induce a myeloproliferative disease in a murine BMT model, and PDGFβR residues Y579/581 are required for this phenotype.
Details
- Title: Subtitle
- Fatal myeloproliferation, induced in mice by TEL/PDGFβR expression, depends on PDGFβR tyrosines 579/581
- Creators
- Michael H Tomasson - Department of Medicine, Brigham and Women’s Hospital, Harvard Institutes of Medicine, Boston, Massachusetts 02115, USADavid W Sternberg - Department of Medicine, Brigham and Women’s Hospital, Harvard Institutes of Medicine, Boston, Massachusetts 02115, USAIfor R Williams - Department of Medicine, Brigham and Women’s Hospital, Harvard Institutes of Medicine, Boston, Massachusetts 02115, USAMartin Carroll - Department of Medicine, Brigham and Women’s Hospital, Harvard Institutes of Medicine, Boston, Massachusetts 02115, USADanielle Cain - Department of Medicine, Brigham and Women’s Hospital, Harvard Institutes of Medicine, Boston, Massachusetts 02115, USAJon C Aster - Department of Medicine, Brigham and Women’s Hospital, Harvard Institutes of Medicine, Boston, Massachusetts 02115, USARobert L Ilaria - Department of Medicine, Brigham and Women’s Hospital, Harvard Institutes of Medicine, Boston, Massachusetts 02115, USARichard A. Van Etten - Department of Medicine, Brigham and Women’s Hospital, Harvard Institutes of Medicine, Boston, Massachusetts 02115, USAD. Gary Gilliland - Department of Medicine, Brigham and Women’s Hospital, Harvard Institutes of Medicine, Boston, Massachusetts 02115, USA
- Resource Type
- Journal article
- Publication Details
- The Journal of clinical investigation, Vol.105(4), pp.423-432
- Publisher
- American Society for Clinical Investigation
- DOI
- 10.1172/JCI8902
- PMID
- 10683371
- PMCID
- PMC289168
- ISSN
- 0021-9738
- eISSN
- 1558-8238
- Language
- English
- Date published
- 02/15/2000
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984094328102771
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