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

来源：

BLOOD | 2012年 / 120卷 / 05期

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

页码：1130 / 1136

页数：7

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