Mll partial tandem duplication and Flt3 internal tandem duplication in a double knock-in mouse recapitulates features of counterpart human acute myeloid leukemias

被引:66
作者
Zorko, Nicholas A. [1 ,2 ]
Bernot, Kelsie M. [3 ]
Whitman, Susan P. [3 ]
Siebenaler, Ronald F. [1 ]
Ahmed, Elshafa H. [3 ]
Marcucci, Gabriele G. [1 ]
Yanes, Daniel A. [3 ]
McConnell, Kathleen K. [3 ]
Mao, Charlene [3 ]
Kalu, Chidimma [1 ]
Zhang, Xiaoli [4 ]
Jarjoura, David [4 ]
Dorrance, Adrienne M. [3 ]
Heerema, Nyla A. [5 ]
Lee, Benjamin H. [6 ]
Huang, Gang [7 ]
Marcucci, Guido [1 ,2 ,3 ,8 ,9 ]
Caligiuri, Michael A. [1 ,2 ,3 ,8 ,9 ]
机构
[1] Ohio State Univ, Coll Med, Columbus, OH 43210 USA
[2] Ohio State Univ, Integrated Biomed Grad Program, Columbus, OH 43210 USA
[3] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA
[4] Ohio State Univ, Ctr Biostat, Columbus, OH 43210 USA
[5] Ohio State Univ, Dept Pathol, Columbus, OH 43210 USA
[6] Novartis Inst Biomed Res, Cambridge, MA USA
[7] Cincinnati Childrens Hosp, Dept Expt Hematol, Cincinnati, OH USA
[8] Ohio State Univ, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA
[9] Ohio State Univ, Div Hematol, Columbus, OH 43210 USA
关键词
WILD-TYPE ALLELE; STUDY-GROUP ULM; NORMAL CYTOGENETICS; ADULT PATIENTS; PROGNOSTIC-SIGNIFICANCE; POOR-PROGNOSIS; GROUP-B; MUTATIONS; GENE; MODEL;
D O I
10.1182/blood-2012-03-415067
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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. Mll(PTD/WT):Flt3(ITD/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, Mll(PTD/WT): Flt3(ITD/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. (Blood. 2012; 120(5): 1130-1136)
引用
收藏
页码:1130 / 1136
页数:7
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