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

Nicholas A. Zorko, 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

Research output: Contribution to journalArticlepeer-review

47 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1130-1136
Number of pages7
JournalBlood
Volume120
Issue number5
DOIs
StatePublished - Aug 2 2012

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