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

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

  • Blood. 2012 Aug 2;120(5):1130-6. doi: 10.1182/blood-2012-03-415067.
Nicholas A Zorko 1 Kelsie M Bernot Susan P Whitman Ronald F Siebenaler Elshafa H Ahmed Gabriele G Marcucci Daniel A Yanes Kathleen K McConnell Charlene Mao Chidimma Kalu Xiaoli Zhang David Jarjoura Adrienne M Dorrance Nyla A Heerema Benjamin H Lee Gang Huang Guido Marcucci Michael A Caligiuri
Affiliations

Affiliation

  • 1 College of Medicine, The Ohio State University, Columbus, OH 43210, USA.
Abstract

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.

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