NPMc+ cooperates with Flt3/ITD mutations to cause acute leukemia recapitulating human disease

Exp Hematol. 2014 Feb;42(2):101-13.e5. doi: 10.1016/j.exphem.2013.10.005. Epub 2013 Oct 29.

Abstract

Cytoplasmic nucleophosmin (NPMc(+)) mutations and FMS-like tyrosine kinase 3 (FLT3) internal tandem duplication (ITD) mutations are two of the most common known molecular alterations in acute myeloid leukemia (AML); they frequently occur together, suggesting cooperative leukemogenesis. To explore the specific relationship between NPMc+ and FLT3/ITD in vivo, we crossed Flt3/ITD knock-in mice with transgenic NPMc+ mice. Mice with both mutations develop a transplantable leukemia of either myeloid or lymphoid lineage, definitively demonstrating cooperation between Flt3/ITD and NPMc+. In mice with myeloid leukemia, functionally significant loss of heterozygosity of the wild-type Flt3 allele is common, similar to what is observed in human FLT3/ITD+ AML, providing further in vivo evidence of the importance of loss of wild-type FLT3 in leukemic initiation and progression. Additionally, in vitro clonogenic assays reveal that the combination of Flt3/ITD and NPMc+ mutations causes a profound monocytic expansion, in excess of that seen with either mutation alone consistent with the predominance of myelomonocytic phenotype in human FLT3/ITD+/NPMc+ AML. This in vivo model of Flt3/ITD+/NPMc+ leukemia closely recapitulates human disease and will therefore serve as a tool for the investigation of the biology of this common disease entity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Animals
  • Cytoplasm / metabolism*
  • Gene Duplication
  • Leukemia, Myeloid, Acute / genetics*
  • Loss of Heterozygosity
  • Mice
  • Mice, Transgenic
  • Mutation*
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • fms-Like Tyrosine Kinase 3 / genetics*

Substances

  • Nuclear Proteins
  • nucleophosmin
  • Flt3 protein, mouse
  • fms-Like Tyrosine Kinase 3