PMID- 22323452
OWN - NLM
STAT- MEDLINE
DCOM- 20120507
LR  - 20211021
IS  - 1528-0020 (Electronic)
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 119
IP  - 12
DP  - 2012 Mar 22
TI  - Knock-in of a FLT3/ITD mutation cooperates with a NUP98-HOXD13 fusion to generate 
      acute myeloid leukemia in a mouse model.
PG  - 2883-94
LID - 10.1182/blood-2011-10-382283 [doi]
AB  - Constitutive activation of FLT3 by internal tandem duplication (ITD) is one of 
      the most common molecular alterations in acute myeloid leukemia (AML). FLT3/ITD 
      mutations have also been observed in myelodysplastic syndrome patients both 
      before and during progression to AML. Previous work has shown that insertion of 
      an FLT3/ITD mutation into the murine Flt3 gene induces a myeloproliferative 
      neoplasm, but not progression to acute leukemia, suggesting that additional 
      cooperating events are required. We therefore combined the FLT3/ITD mutation with 
      a model of myelodysplastic syndrome involving transgenic expression of the 
      Nup98-HoxD13 (NHD13) fusion gene. Mice expressing both the FLT3/ITD and NHD13 
      transgene developed AML with 100% penetrance and short latency. These leukemias 
      were driven by mutant FLT3 expression and were susceptible to treatment with FLT3 
      tyrosine kinase inhibitors. We also observed a spontaneous loss of the wild-type 
      Flt3 allele in these AMLs, further modeling the loss of the heterozygosity 
      phenomenon that is seen in human AML with FLT3-activating mutations. Because 
      resistance to FLT3 inhibitors remains an important clinical issue, this model may 
      help identify new molecular targets in collaborative signaling pathways.
FAU - Greenblatt, Sarah
AU  - Greenblatt S
AD  - Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, 
      MD, USA.
FAU - Li, Li
AU  - Li L
FAU - Slape, Christopher
AU  - Slape C
FAU - Nguyen, Bao
AU  - Nguyen B
FAU - Novak, Rachel
AU  - Novak R
FAU - Duffield, Amy
AU  - Duffield A
FAU - Huso, David
AU  - Huso D
FAU - Desiderio, Stephen
AU  - Desiderio S
FAU - Borowitz, Michael J
AU  - Borowitz MJ
FAU - Aplan, Peter
AU  - Aplan P
FAU - Small, Donald
AU  - Small D
LA  - eng
GR  - P01 AI072677/AI/NIAID NIH HHS/United States
GR  - R01 CA090668/CA/NCI NIH HHS/United States
GR  - P01 CA070970/CA/NCI NIH HHS/United States
GR  - CA70970/CA/NCI NIH HHS/United States
GR  - ImNIH/Intramural NIH HHS/United States
GR  - CA90668/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, N.I.H., Intramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20120208
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (Homeodomain Proteins)
RN  - 0 (Nuclear Pore Complex Proteins)
RN  - 0 (Oncogene Proteins, Fusion)
RN  - 0 (homeobox protein HOXA13)
RN  - 0 (nuclear pore complex protein 98)
RN  - EC 2.7.10.1 (Flt3 protein, mouse)
RN  - EC 2.7.10.1 (fms-Like Tyrosine Kinase 3)
SB  - IM
MH  - Animals
MH  - Blotting, Western
MH  - *Disease Models, Animal
MH  - Flow Cytometry
MH  - Gene Knock-In Techniques
MH  - Homeodomain Proteins/*genetics
MH  - Humans
MH  - Leukemia, Myeloid, Acute/*genetics
MH  - Mice
MH  - Mice, Transgenic
MH  - Mutation
MH  - Nuclear Pore Complex Proteins/*genetics
MH  - Oncogene Proteins, Fusion/*genetics
MH  - Real-Time Polymerase Chain Reaction
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - fms-Like Tyrosine Kinase 3/*genetics
PMC - PMC3327463
EDAT- 2012/02/11 06:00
MHDA- 2012/05/09 06:00
PMCR- 2013/03/22
CRDT- 2012/02/11 06:00
PHST- 2012/02/11 06:00 [entrez]
PHST- 2012/02/11 06:00 [pubmed]
PHST- 2012/05/09 06:00 [medline]
PHST- 2013/03/22 00:00 [pmc-release]
AID - S0006-4971(20)49221-3 [pii]
AID - 2011/382283 [pii]
AID - 10.1182/blood-2011-10-382283 [doi]
PST - ppublish
SO  - Blood. 2012 Mar 22;119(12):2883-94. doi: 10.1182/blood-2011-10-382283. Epub 2012 
      Feb 8.