The cytoplasmic NPM mutant induces myeloproliferation in a transgenic mouse model.
Although NPM1 gene mutations leading to aberrant cytoplasmic expression of nucleophosmin (NPMc(+)) are the most frequent genetic lesions in acute myeloid leukemia, there is yet no experimental model demonstrating their oncogenicity in vivo. We report the generation and characterization of a transgenic mouse model expressing the most frequent human NPMc(+) mutation driven by the myeloid-specific human MRP8 promoter (hMRP8-NPMc(+)). In parallel, we generated a similar wild-type NPM trans-genic model (hMRP8-NPM). Interestingly, hMRP8-NPMc(+) transgenic mice developed myeloproliferation in bone marrow and spleen, whereas nontransgenic littermates and hMRP8-NPM transgenic mice remained disease free. These findings provide the first in vivo evidence indicating that NPMc(+) confers a proliferative advantage in the myeloid lineage. No spontaneous acute myeloid leukemia was found in hMPR8-NPMc(+) or hMRP8-NPM mice. This model will also aid in the development of therapeutic regimens that specifically target NPMc(+).
Cheng
Ke
K
Cancer Genetics Program, Beth Israel Deaconess Cancer Center and Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.
Sportoletti
Paolo
P
Ito
Keisuke
K
Clohessy
John G
JG
Teruya-Feldstein
Julie
J
Kutok
Jeffery L
JL
Pandolfi
Pier Paolo
PP
D000818:Animals; D015153:Blotting, Western; D002469:Cell Separation; D003593:Cytoplasm / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D005434:Flow Cytometry; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D009154:Mutation; D022423:Myeloid Cells / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D000090243:Nucleophosmin; D011401:Promoter Regions, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction
C000716967:NPM1 protein, human; C000715570:Npm1 protein, mouse; D009687:Nuclear Proteins; D000090243:Nucleophosmin