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Potent co-operation between the NUP98-NSD1 fusion and the FLT3-ITD mutation in acute myeloid leukemia induction.
Journal article

Potent co-operation between the NUP98-NSD1 fusion and the FLT3-ITD mutation in acute myeloid leukemia induction.

  • Thanasopoulou A Department of Biomedicine, University Children's Hospital of Basel (UKBB), Switzerland.
  • Tzankov A Institute for Pathology, University Hospital Basel, Switzerland.
  • Schwaller J Department of Biomedicine, University Children's Hospital of Basel (UKBB), Switzerland j.schwaller@unibas.ch.
  • 2014-06-22
Published in:
  • Haematologica. - 2014
Animals
Cell Proliferation
Cell Transformation, Neoplastic
Gene Expression Regulation, Neoplastic
Genetic Vectors
Homeodomain Proteins
Humans
Leukemia, Myeloid, Acute
Mesenchymal Stem Cells
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mutation
Oncogene Proteins, Fusion
Primary Cell Culture
Protein Kinase Inhibitors
Protein Structure, Tertiary
Retroviridae
Signal Transduction
Transduction, Genetic
Translocation, Genetic
fms-Like Tyrosine Kinase 3
English The NUP98-NSD1 fusion, product of the t(5;11)(q35;p15.5) chromosomal translocation, is one of the most prevalent genetic alterations in cytogenetically normal pediatric acute myeloid leukemias and is associated with poor prognosis. Co-existence of an FLT3-ITD activating mutation has been found in more than 70% of NUP98-NSD1-positive patients. To address functional synergism, we determined the transforming potential of retrovirally expressed NUP98-NSD1 and FLT3-ITD in the mouse. Expression of NUP98-NSD1 provided mouse strain-dependent, aberrant self-renewal potential to bone marrow progenitor cells. Co-expression of FLT3-ITD increased proliferation and maintained self-renewal in vitro. Transplantation of immortalized progenitors co-expressing NUP98-NSD1 and FLT3-ITD into mice resulted in acute myeloid leukemia after a short latency. In contrast, neither NUP98-NSD1 nor FLT3-ITD single transduced cells were able to initiate leukemia. Interestingly, as reported for patients carrying NUP98-NSD1, an increased Flt3-ITD to wild-type Flt3 mRNA expression ratio with increased FLT3-signaling was associated with rapidly induced disease. In contrast, there was no difference in the expression levels of the NUP98-NSD1 fusion or its proposed targets HoxA5, HoxA7, HoxA9 or HoxA10 between animals with different latencies to develop disease. Finally, leukemic cells co-expressing NUP98-NSD1 and FLT3-ITD were very sensitive to a small molecule FLT3 inhibitor, which underlines the significance of aberrant FLT3 signaling for NUP98-NSD1-positive leukemias and suggests new therapeutic approaches that could potentially improve patient outcome.
Language
  • English
Open access status
gold
Identifiers
Persistent URL
https://sonar.ch/global/documents/160005
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