TY - JOUR
T1 - The cytoplasmic NPM mutant induces myeloproliferation in a transgenic mouse model
AU - Cheng, Ke
AU - Sportoletti, Paolo
AU - Ito, Keisuke
AU - Clohessy, John G.
AU - Teruya-Feldstein, Julie
AU - Kutok, Jeffery L.
AU - Pandolfi, Pier Paolo
PY - 2010/4/22
Y1 - 2010/4/22
N2 - 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 transgenic model (hMRP8-NPM). Interestingly, hMRP8-NPMc+ transgenic mice developed myeloproliferation in bone marrow and spleen, whereas nontransgenic litter-mates 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+.
AB - 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 transgenic model (hMRP8-NPM). Interestingly, hMRP8-NPMc+ transgenic mice developed myeloproliferation in bone marrow and spleen, whereas nontransgenic litter-mates 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+.
UR - http://www.scopus.com/inward/record.url?scp=77951443641&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77951443641&partnerID=8YFLogxK
U2 - 10.1182/blood-2009-03-208587
DO - 10.1182/blood-2009-03-208587
M3 - Article
C2 - 19666870
AN - SCOPUS:77951443641
SN - 0006-4971
VL - 115
SP - 3341
EP - 3345
JO - Blood
JF - Blood
IS - 16
ER -