Mll partial tandem duplication and Flt3 internal tandem duplication in a double knock-in mouse recapitulates features of counterpart human acute myeloid leukemias.
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.
College of Medicine, The Ohio State University, Columbus, OH 43210, USA.
Nicholas A
NA
Zorko
Kelsie M
KM
Bernot
Susan P
SP
Whitman
Ronald F
RF
Siebenaler
Elshafa H
EH
Ahmed
Gabriele G
GG
Marcucci
Daniel A
DA
Yanes
Kathleen K
KK
McConnell
Charlene
C
Mao
Chidimma
C
Kalu
Xiaoli
X
Zhang
David
D
Jarjoura
Adrienne M
AM
Dorrance
Nyla A
NA
Heerema
Benjamin H
BH
Lee
Gang
G
Huang
Guido
G
Marcucci
Michael A
MA
Caligiuri
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004195:Disease Models, Animal; D020440:Gene Duplication / Q000502:physiology*; D055879:Gene Knock-In Techniques; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D020080:Tandem Repeat Sequences / Q000235:genetics; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics*
C497422:KMT2A protein, human; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3