TY - JOUR
T1 - Mll partial tandem duplication and Flt3 internal tandem duplication in a double knock-in mouse recapitulates features of counterpart human acute myeloid leukemias
AU - Zorko, Nicholas A.
AU - Bernot, Kelsie M.
AU - Whitman, Susan P.
AU - Siebenaler, Ronald F.
AU - Ahmed, Elshafa H.
AU - Marcucci, Gabriele G.
AU - Yanes, Daniel A.
AU - McConnell, Kathleen K.
AU - Mao, Charlene
AU - Kalu, Chidimma
AU - Zhang, Xiaoli
AU - Jarjoura, David
AU - Dorrance, Adrienne M.
AU - Heerema, Nyla A.
AU - Lee, Benjamin H.
AU - Huang, Gang
AU - Marcucci, Guido
AU - Caligiuri, Michael A.
PY - 2012/8/2
Y1 - 2012/8/2
N2 - The MLL-partial tandem duplication (PTD) associates with high-risk cytogenetically normal acute myeloid leukemia (AML). Concurrent presence of FLT3-internal tandem duplication (ITD) is observed in 25% of patients with MLL-PTD AML. However, mice expressing either Mll-PTD or Flt3-ITD do not develop AML, suggesting that 2 mutations are necessary for the AML phenotype. Thus, we generated a mouse expressing both Mll-PTD and Flt3-ITD. MllPTD/WT: Flt3ITD/WT mice developed acute leukemia with 100% penetrance, at a median of 49 weeks. As in human MLL-PTD and/or the FLT3-ITD AML, mouse blasts exhibited normal cytogenetics, decreased Mll-WT-to-Mll-PTD ratio, loss of the Flt3-WT allele, and increased total Flt3. Highlighting the adverse impact of FLT3-ITD dosage on patient survival, mice with homozygous Flt3-ITD alleles, MllPTD/WT:Flt3ITD/ITD, demonstrated a nearly 30-week reduction in latency to overt AML. Here we demonstrate, for the first time, that Mll-PTD contributes to leukemogenesis as a gain-of-function mutation and describe a novel murine model closely recapitulating human AML.
AB - The MLL-partial tandem duplication (PTD) associates with high-risk cytogenetically normal acute myeloid leukemia (AML). Concurrent presence of FLT3-internal tandem duplication (ITD) is observed in 25% of patients with MLL-PTD AML. However, mice expressing either Mll-PTD or Flt3-ITD do not develop AML, suggesting that 2 mutations are necessary for the AML phenotype. Thus, we generated a mouse expressing both Mll-PTD and Flt3-ITD. MllPTD/WT: Flt3ITD/WT mice developed acute leukemia with 100% penetrance, at a median of 49 weeks. As in human MLL-PTD and/or the FLT3-ITD AML, mouse blasts exhibited normal cytogenetics, decreased Mll-WT-to-Mll-PTD ratio, loss of the Flt3-WT allele, and increased total Flt3. Highlighting the adverse impact of FLT3-ITD dosage on patient survival, mice with homozygous Flt3-ITD alleles, MllPTD/WT:Flt3ITD/ITD, demonstrated a nearly 30-week reduction in latency to overt AML. Here we demonstrate, for the first time, that Mll-PTD contributes to leukemogenesis as a gain-of-function mutation and describe a novel murine model closely recapitulating human AML.
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U2 - 10.1182/blood-2012-03-415067
DO - 10.1182/blood-2012-03-415067
M3 - Article
C2 - 22674806
AN - SCOPUS:84864565435
SN - 0006-4971
VL - 120
SP - 1130
EP - 1136
JO - Blood
JF - Blood
IS - 5
ER -