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 A Brown

Research output: Contribution to journalArticle

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.

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ASJC Scopus subject areas

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

Cite this

NPMc+ cooperates with Flt3/ITD mutations to cause acute leukemia recapitulating human disease. / 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, Patrick A.

In: Experimental Hematology, Vol. 42, No. 2, 02.2014, p. 101-113.

Research output: Contribution to journalArticle