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ZFIN ID: ZDB-PUB-120705-6
Alternate TEL-JAK2 fusions associated with T cell acute lymphoblastic leukemia and atypical chronic myelogenous leukemia dissected in zebrafish
Onnebo, S.M., Rasighaemi, P., Kumar, J., Liongue, C., and Ward, A.C.
Date: 2012
Source: Haematologica 97(12): 1895-1903 (Journal)
Registered Authors: Rasighaemi, Parisa, Ward, Alister C.
Keywords: Chronic Myelogenous Leukemia, Pediatric Acute Lymphoblastic Leukemia, Adult Acute Lymphoblastic Leukemia, Cytogenetics and Molecular Genetics, TEL-JAK2
MeSH Terms:
  • Animals
  • Cell Lineage
  • Cells, Cultured
  • Embryo, Nonmammalian/metabolism
  • Embryo, Nonmammalian/pathology
  • Humans
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics*
  • Mutation/genetics
  • Oncogene Proteins, Fusion/genetics*
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics*
  • Protein-Tyrosine Kinases/genetics*
  • Transcription Factors/genetics*
  • Zebrafish/genetics*
  • Zebrafish Proteins/genetics*
PubMed: 22733019 Full text @ Haematologica
FIGURES
ABSTRACT

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. This study investigated potential differences between these alternate TEL-JAK2 fusions, including their lineage specificity. Design and Methods: Both T-cell acute lymphoblastic leukemia and atypical chronic myelogenous leukemia derived TEL-JAK2 fusion types 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 alternate 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 alternate 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 alternate 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 signalling.

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