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A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
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Published on: December 7, 2014

Novel activating JAK2 mutation in a patient with Down syndrome and B-cell precursor acute lymphoblastic leukemia

Sebastien Malinge1, Raouf Ben-Abdelali, Catherine Settegrana

  • 1Institut National de la Santé et de la Recherche Scientifique (INSERM), E0210, Paris, France.

Blood
|October 28, 2006
PubMed

Insights

Researchers discovered a new Janus kinase 2 (JAK2) mutation in a patient with Down syndrome and acute lymphoblastic leukemia. This JAK2 mutation activates the JAK-STAT pathway, potentially contributing to lymphoid malignancies in children with Down syndrome.

Area of Science:

  • Oncology
  • Genetics
  • Molecular Biology

Background:

  • Tyrosine kinase gene activation is common in hematologic malignancies.
  • Gene activation may stem from gene dysregulation, prompting screening for mutations via high-level gene expression.

Purpose of the Study:

  • To screen for activating mutations in the Janus kinase 2 (JAK2) gene in acute leukemia cases.
  • To investigate the role of JAK2 mutations in Down syndrome-associated hematologic disorders.

Main Methods:

  • Focused on the JAK2 gene in 90 acute leukemia samples.
  • Identified a novel JAK2 mutation (JAK2DeltaIREED) in a patient with Down syndrome and B-cell precursor acute lymphoblastic leukemia (BCP-ALL).
  • Expressed JAK2DeltaIREED in Ba/F3 cells to assess pathway activation and proliferation.

Main Results:

  • A novel 5-amino acid deletion (JAK2DeltaIREED) in the JH2 pseudokinase domain was identified.
  • JAK2DeltaIREED expression led to constitutive activation of the JAK-STAT pathway.
  • Induced growth factor-independent cell proliferation in Ba/F3 cells.

Conclusions:

  • The JAK2 pseudokinase domain is an oncogenic hotspot.
  • JAK-STAT pathway activation may contribute to lymphoid malignancies and hematologic disorders in children with Down syndrome.

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