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

نویسندگان

  • 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
چکیده

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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عنوان ژورنال:
  • Blood

دوره 120 5  شماره 

صفحات  -

تاریخ انتشار 2012