BACKGROUND: Chromosomal translocations resulting in alternative fusions of the human TEL (ETV6) and JAK2 genes have been observed in cases of acute lymphoblastic leukemia and chronic myelogenous leukemia, but a full understanding of their role in disease etiology has remained elusive. In this study potential differences between these alternative TEL-JAK2 fusions, including their lineage specificity, were investigated. DESIGN AND METHODS: TEL-JAK2 fusion types derived from both T-cell acute lymphoblastic leukemia and atypical chronic myelogenous leukemia were generated using the corresponding zebrafish tel and jak2a genes and placed under the control of either the white blood cell-specific spi1 promoter or the ubiquitously-expressed cytomegalovirus promoter. These constructs were injected into zebrafish embryos and their effects on hematopoiesis examined using a range of molecular approaches. In addition, the functional properties of the alternative fusions were investigated in vitro. RESULTS: Injection of the T-cell acute lymphoblastic leukemia-derived tel-jak2a significantly perturbed lymphopoiesis with a lesser effect on myelopoiesis in zebrafish embryos. In contrast, injection of the atypical chronic myelogenous leukemia-derived tel-jak2a resulted in significant perturbation of the myeloid compartment. These phenotypes were observed regardless of whether expressed in a white blood cell-specific or ubiquitous manner, with no overt cellular proliferation outside of the hematopoietic cells. Functional studies revealed subtle differences between the alternative forms, with the acute lymphoblastic leukemia variant showing higher activity, but reduced downstream signal transducer and activator of transcription activation and decreased sensitivity to JAK2 inhibition. JAK2 activity was required to mediate the effects of both variants on zebrafish hematopoiesis. CONCLUSIONS: This study indicates that the molecular structure of alternative TEL-JAK2 fusions likely contributes to the etiology of disease. The data further suggest that this class of oncogene exerts its effects in a cell lineage-specific manner, which may be due to differences in downstream signaling.
BACKGROUND: Chromosomal translocations resulting in alternative fusions of the humanTEL (ETV6) and JAK2 genes have been observed in cases of acute lymphoblastic leukemia and chronic myelogenous leukemia, but a full understanding of their role in disease etiology has remained elusive. In this study potential differences between these alternative TEL-JAK2 fusions, including their lineage specificity, were investigated. DESIGN AND METHODS: TEL-JAK2 fusion types derived from both T-cell acute lymphoblastic leukemia and atypical chronic myelogenous leukemia were generated using the corresponding zebrafishtel and jak2a genes and placed under the control of either the white blood cell-specific spi1 promoter or the ubiquitously-expressed cytomegalovirus promoter. These constructs were injected into zebrafish embryos and their effects on hematopoiesis examined using a range of molecular approaches. In addition, the functional properties of the alternative fusions were investigated in vitro. RESULTS: Injection of the T-cell acute lymphoblastic leukemia-derived tel-jak2a significantly perturbed lymphopoiesis with a lesser effect on myelopoiesis in zebrafish embryos. In contrast, injection of the atypical chronic myelogenous leukemia-derived tel-jak2a resulted in significant perturbation of the myeloid compartment. These phenotypes were observed regardless of whether expressed in a white blood cell-specific or ubiquitous manner, with no overt cellular proliferation outside of the hematopoietic cells. Functional studies revealed subtle differences between the alternative forms, with the acute lymphoblastic leukemia variant showing higher activity, but reduced downstream signal transducer and activator of transcription activation and decreased sensitivity to JAK2 inhibition. JAK2 activity was required to mediate the effects of both variants on zebrafishhematopoiesis. CONCLUSIONS: This study indicates that the molecular structure of alternative TEL-JAK2 fusions likely contributes to the etiology of disease. The data further suggest that this class of oncogene exerts its effects in a cell lineage-specific manner, which may be due to differences in downstream signaling.
Authors: Chloé James; Valérie Ugo; Jean-Pierre Le Couédic; Judith Staerk; François Delhommeau; Catherine Lacout; Loïc Garçon; Hana Raslova; Roland Berger; Annelise Bennaceur-Griscelli; Jean Luc Villeval; Stefan N Constantinescu; Nicole Casadevall; William Vainchenker Journal: Nature Date: 2005-04-28 Impact factor: 49.962
Authors: J Schwaller; J Frantsve; J Aster; I R Williams; M H Tomasson; T S Ross; P Peeters; L Van Rompaey; R A Van Etten; R Ilaria; P Marynen; D G Gilliland Journal: EMBO J Date: 1998-09-15 Impact factor: 11.598
Authors: E Joanna Baxter; Linda M Scott; Peter J Campbell; Clare East; Nasios Fourouclas; Soheila Swanton; George S Vassiliou; Anthony J Bench; Elaine M Boyd; Natasha Curtin; Mike A Scott; Wendy N Erber; Anthony R Green Journal: Lancet Date: 2005 Mar 19-25 Impact factor: 79.321
Authors: Robert Kralovics; Francesco Passamonti; Andreas S Buser; Soon-Siong Teo; Ralph Tiedt; Jakob R Passweg; Andre Tichelli; Mario Cazzola; Radek C Skoda Journal: N Engl J Med Date: 2005-04-28 Impact factor: 91.245
Authors: A C Oates; A Brownlie; S J Pratt; D V Irvine; E C Liao; B H Paw; K J Dorian; S L Johnson; J H Postlethwait; L I Zon; A F Wilks Journal: Blood Date: 1999-10-15 Impact factor: 22.113