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

Rachel Rau; Daniel Magoon; Sarah Greenblatt; Li Li; Colleen Annesley; Amy S Duffield; David Huso; Emily McIntyre; John G Clohessy; Markus Reschke; Pier Paolo Pandolfi; Donald Small; Patrick Brown

doi:10.1016/j.exphem.2013.10.005

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.

Authors

Affiliations

¹ Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA. Electronic address: [email protected].
² Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
³ Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁴ Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁵ Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁶ Cancer Genetics Program, Beth Israel Deaconess Cancer Center and Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.

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
Nucleophosmin
Reverse Transcriptase Polymerase Chain Reaction
fms-Like Tyrosine Kinase 3 / genetics*

Substances

NPM1 protein, human
Nuclear Proteins
Nucleophosmin
Flt3 protein, mouse
fms-Like Tyrosine Kinase 3

Abstract

Publication types

MeSH terms

Substances

Grants and funding