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

Authors: Rau, R  Magoon, D  Greenblatt, S  Li, L  Annesley, C  Duffield, AS  Huso, D  McIntyre, E  Clohessy, JG  Reschke, M  Pandolfi, PP  Small, D  Brown, P 
Citation: Rau R, etal., Exp Hematol. 2014 Feb;42(2):101-13.e5. doi: 10.1016/j.exphem.2013.10.005. Epub 2013 Oct 29.
Pubmed: (View Article at PubMed) PMID:24184354
DOI: Full-text: DOI:10.1016/j.exphem.2013.10.005

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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CRRD Object Information
CRRD ID: 11049471
Created: 2016-04-06
Species: All species
Last Modified: 2016-04-06
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.