TY - JOUR
T1 - NPMc+ cooperates with Flt3/ITD mutations to cause acute leukemia recapitulating human disease
AU - Rau, Rachel
AU - Magoon, Daniel
AU - Greenblatt, Sarah
AU - Li, Li
AU - Annesley, Colleen
AU - Duffield, Amy S.
AU - Huso, David
AU - McIntyre, Emily
AU - Clohessy, John G.
AU - Reschke, Markus
AU - Pandolfi, Pier Paolo
AU - Small, Donald
AU - Brown, Patrick
N1 - Funding Information:
The authors thank the members of the Brown laboratory (Eric Schafer, Edward Allan Sison, Sandeep Negi, and Allison Kaeding) and the members of the Small lab for providing informative discussion and helpful suggestions. This work was funded in part through The St. Baldrick's Foundation (Post-Doctoral Fellowship for Childhood Cancer Research Award, to R.R.); Leukemia and Lymphoma Society (Translational Research Program Grant, Scholar in Clinical Research Award, to P.B.); National Cancer Institute ( K23 CA111728 , to P.B.; R01CA90668 , P01CA70970 , to D.S.), Damon Runyon Cancer Research Foundation (Clinical Investigator Award, to P.B.) and Giant Food Children's Cancer Research Fund .
PY - 2014/2
Y1 - 2014/2
N2 - 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.
AB - 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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U2 - 10.1016/j.exphem.2013.10.005
DO - 10.1016/j.exphem.2013.10.005
M3 - Article
C2 - 24184354
AN - SCOPUS:84896692359
SN - 0301-472X
VL - 42
SP - 101-113.e5
JO - Experimental Hematology
JF - Experimental Hematology
IS - 2
ER -