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  • The EMBO Journal (1998) 17, 5321 - 5333
  • doi:10.1093/emboj/17.18.5321

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

Juerg Schwaller1, Julie Frantsve1, Jon Aster2, Ifor R. Williams3, Michael H. Tomasson1, Theodora S. Ross1, Pieter Peeters4, Luc Van Rompaey4, Richard A. Van Etten1,5, Robert Ilaria Jr1, Peter Marynen4 and D.Gary Gilliland1,6

  1. Division of Hematology and Oncology, Harvard Medical School, Boston, MA 02115, USA
  2. Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
  3. Department of Pathology, Emory University, Atlanta, GA, USA
  4. The Center of Human Genetics, University of Leuven, Belgium
  5. Center for Blood Research, Department of Genetics, Boston, MA 02115, USA
  6. The Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA

Correspondence to:

D.Gary Gilliland, E-mail: gilliland@calvin.bwh.harvard.edu

Received 16 February 1998; Accepted 20 July 1998; Revised 20 July 1998

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.

  • Keywords:

    • animal model,
    • leukemogenesis,
    • Stat 5,
    • TEL–JAK2 fusion gene,
    • transformation