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

Authors
  • Rau, Rachel
  • Magoon, Daniel
  • Greenblatt, Sarah
  • Li, Li
  • Annesley, Colleen
  • Duffield, Amy S.
  • Huso, David
  • McIntyre, Emily
  • Clohessy, John G.
  • Reschke, Markus
  • Pandolfi, Pier Paolo
  • Small, Donald
  • Brown, Patrick1, 2, 3, 4, 5, 1, 5, 6, 5, 7, 5, 8, 9, 10
  • 1 Department of Pediatrics
  • 2 Baylor College of Medicine
  • 3 Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
  • 4 Department of Oncology
  • 5 Johns Hopkins University School of Medicine
  • 6 Department of Pathology
  • 7 Department of Molecular and Comparative Pathobiology
  • 8 Cancer Genetics Program
  • 9 Beth Israel Deaconess Cancer Center and Department of Medicine
  • 10 Beth Israel Deaconess Medical Center
Type
Published Article
Journal
Experimental Hematology
Publisher
Elsevier
Publication Date
Jan 01, 2014
Accepted Date
Oct 22, 2013
Volume
42
Issue
2
Pages
101–113
Identifiers
DOI: 10.1016/j.exphem.2013.10.005
Source
Elsevier
License
Unknown

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.

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