title: Potent co-operation between the NUP98-NSD1 fusion and the FLT3-ITD mutation in acute myeloid leukemia induction.
abstract: 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.
authors.affiliation: Department of Biomedicine, University Children's Hospital of Basel (UKBB), Switzerland.
authors.forename: Angeliki
authors.initials: A
authors.lastname: Thanasopoulou
authors.affiliation: Institute for Pathology, University Hospital Basel, Switzerland.
authors.forename: Alexandar
authors.initials: A
authors.lastname: Tzankov
authors.affiliation: Department of Biomedicine, University Children's Hospital of Basel (UKBB), Switzerland j.schwaller@unibas.ch.
authors.forename: Juerg
authors.initials: J
authors.lastname: Schwaller
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D005822:Genetic Vectors; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009154:Mutation; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D061251:Primary Cell Culture; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D012190:Retroviridae / Q000235:genetics; D015398:Signal Transduction; D014161:Transduction, Genetic; D014178:Translocation, Genetic; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics* / Q000378:metabolism
chemical_list: D018398:Homeodomain Proteins; C522276:NUP98-NSD1 protein, human; D015514:Oncogene Proteins, Fusion; D047428:Protein Kinase Inhibitors; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3