Journal article
Transformation of hematopoietic cell lines to growth‐factor independence and induction of a fatal myelo‐ and lymphoproliferative disease in mice by retrovirally transduced TEL/JAK2 fusion genes
The EMBO journal, Vol.17(18), pp.5321-5333
09/15/1998
DOI: 10.1093/emboj/17.18.5321
PMCID: PMC1170859
PMID: 9736611
Abstract
Recent reports have demonstrated fusion of the TEL gene on 12p13 to the JAK2 gene on 9p24 in human leukemias. Three variants have been identified that fuse the TEL pointed (PNT) domain to (i) the JAK2 JH1‐kinase domain, (ii) part of and (iii) all of the JH2 pseudokinase domain. We report that all of the human TEL/JAK2 variants, and a human/mouse chimeric hTEL/mJAK2. (JH1) fusion gene, transform the interleukin‐3 (IL‐3)‐dependent murine hematopoietic cell line Ba/F3 to IL‐3‐independent growth. Transformation requires both the TEL PNT domain and JAK2 kinase activity. Furthermore, all TEL/JAK2 variants strongly activated STAT 5 by phosphotyrosine Western blots and by electrophoretic mobility shift assays (EMSA). Mice (n = 40) transplanted with bone marrow infected with the MSCV retrovirus containing either the hTEL/mJAK2. (JH1) fusion or its human counterpart developed a fatal mixed myeloproliferative and T‐cell lymphoproliferative disorder with a latency of 2‐10 weeks. In contrast, mice transplanted with a TEL/JAK2 mutant lacking the TEL PNT domain (n = 10) or a kinase‐inactive TEL/JAK2. (JH1) mutant (n = 10) did not develop the disease. We conclude that all human TEL/JAK2 fusion variants are oncoproteins in vitro that strongly activate STAT 5, and cause lethal myelo‐ and lymphoproliferative syndromes in murine bone marrow transplant models of leukemia.
Details
- Title: Subtitle
- Transformation of hematopoietic cell lines to growth‐factor independence and induction of a fatal myelo‐ and lymphoproliferative disease in mice by retrovirally transduced TEL/JAK2 fusion genes
- Creators
- Juerg Schwaller - Division of Hematology and Oncology, Harvard Medical SchoolJulie Frantsve - Division of Hematology and Oncology, Harvard Medical SchoolJon Aster - Department of Pathology, Brigham and Women's Hospital, Harvard Medical SchoolIfor R Williams - Department of Pathology, Emory UniversityMichael H Tomasson - Division of Hematology and Oncology, Harvard Medical SchoolTheodora S Ross - Division of Hematology and Oncology, Harvard Medical SchoolPieter Peeters - The Center of Human Genetics, University of LeuvenLuc Van Rompaey - The Center of Human Genetics, University of LeuvenRichard A Van Etten - Center for Blood Research, Department of GeneticsRobert Ilaria - Division of Hematology and Oncology, Harvard Medical SchoolPeter Marynen - The Center of Human Genetics, University of LeuvenD.Gary Gilliland - The Howard Hughes Medical Institute, Harvard Medical School
- Resource Type
- Journal article
- Publication Details
- The EMBO journal, Vol.17(18), pp.5321-5333
- Publisher
- John Wiley & Sons, Ltd
- DOI
- 10.1093/emboj/17.18.5321
- PMID
- 9736611
- PMCID
- PMC1170859
- ISSN
- 0261-4189
- eISSN
- 1460-2075
- Number of pages
- 13
- Language
- English
- Date published
- 09/15/1998
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984094361702771
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