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

Research output: Contribution to journalArticlepeer-review

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 invivo, 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 invivo evidence of the importance of loss of wild-type FLT3 in leukemic initiation and progression. Additionally, invitro 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 invivo 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.

Original languageEnglish (US)
Pages (from-to)101-113.e5
JournalExperimental Hematology
Volume42
Issue number2
DOIs
StatePublished - Feb 2014

ASJC Scopus subject areas

  • Molecular Biology
  • Hematology
  • Genetics
  • Cell Biology
  • Cancer Research

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