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 Schwaller, Julie Frantsve, Jon Aster, Ifor R. Williams, Michael H. Tomasson, Theodora S. Ross, Pieter Peeters, Luc Van Rompaey, Richard A. Van Etten, Robert Ilaia, Peter Marynen, D. Gary Gilliland

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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.

Original languageEnglish (US)
Pages (from-to)5321-5333
Number of pages13
JournalEMBO Journal
Volume17
Issue number18
DOIs
StatePublished - Sep 15 1998

Fingerprint

Gene Fusion
Intercellular Signaling Peptides and Proteins
Fusion reactions
Genes
Cells
Cell Line
Phosphotransferases
Interleukin-3
Bone
Leukemia
Electrophoretic mobility
Transplants
Phosphotyrosine
Bone Marrow
T-cells
Oncogene Proteins
Electric fuses
Lymphoproliferative Disorders
Electrophoretic Mobility Shift Assay
Retroviridae

Keywords

  • Animal model
  • Leukemogenesis
  • Stat 5
  • TEL-JAK2 fusion gene
  • Transformation

ASJC Scopus subject areas

  • Genetics
  • Cell Biology

Cite this

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. / Schwaller, Juerg; Frantsve, Julie; Aster, Jon; Williams, Ifor R.; Tomasson, Michael H.; Ross, Theodora S.; Peeters, Pieter; Van Rompaey, Luc; Van Etten, Richard A.; Ilaia, Robert; Marynen, Peter; Gilliland, D. Gary.

In: EMBO Journal, Vol. 17, No. 18, 15.09.1998, p. 5321-5333.

Research output: Contribution to journalArticle

Schwaller, J, Frantsve, J, Aster, J, Williams, IR, Tomasson, MH, Ross, TS, Peeters, P, Van Rompaey, L, Van Etten, RA, Ilaia, R, Marynen, P & Gilliland, DG 1998, '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', EMBO Journal, vol. 17, no. 18, pp. 5321-5333. https://doi.org/10.1093/emboj/17.18.5321
Schwaller, Juerg ; Frantsve, Julie ; Aster, Jon ; Williams, Ifor R. ; Tomasson, Michael H. ; Ross, Theodora S. ; Peeters, Pieter ; Van Rompaey, Luc ; Van Etten, Richard A. ; Ilaia, Robert ; Marynen, Peter ; Gilliland, D. Gary. / 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. In: EMBO Journal. 1998 ; Vol. 17, No. 18. pp. 5321-5333.
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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.",
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T1 - 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

AU - Schwaller, Juerg

AU - Frantsve, Julie

AU - Aster, Jon

AU - Williams, Ifor R.

AU - Tomasson, Michael H.

AU - Ross, Theodora S.

AU - Peeters, Pieter

AU - Van Rompaey, Luc

AU - Van Etten, Richard A.

AU - Ilaia, Robert

AU - Marynen, Peter

AU - Gilliland, D. Gary

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N2 - 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.

AB - 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.

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