Submitted January 17, 2008
Accepted June 25, 2008
The Mll partial tandem duplication: differential, tissue-specific activity in the presence or absence of the wild type allele
Adrienne M Dorrance, Shujun Liu, Anita Chong, Benjamin Pulley, David Nemer, Martin Guimond, Weifeng Yuan, Dennis Chang, Susan P. Whitman, Guido Marcucci, and Michael A. Caligiuri*
Veterinary Biosciences, The Ohio State University, Columbus, OH, United States
Internal Medicine, Division of Hematology and Oncology, The Ohio State University, Columbus, OH, United States
Comprehensive Cancer Center-James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, OH, United States
* Corresponding author; email: michael.caligiuri{at}osumc.edu.
The partial tandem duplication of MLL (MLL-PTD) is found in 5-10% of patients with acute myeloid leukemia (AML) and normal cytogenetics. Its expression in human leukemic blasts is coincident with a silenced wild-type (WT) MLL allele. We therefore generated mice expressing the Mll-PTD in the absence of Mll-WT. These MllPTD/- mice die at birth unlike the normal life expectancy of the MllPTD/WT, MllWT/-, and MllWT/WT mice. Using MllWT/WT fetal liver cells (FLC) as baseline, we compared MllPTD/- with MllPTD/WT FLC and found both had increased HoxA gene expression and CFU-GM progenitors; in contrast, only MllPTD/WT FLC had increased CFU-GEMM progenitors. The similarities between MllPTD/WT and MllPTD/- mice suggest that the Mll-PTD mutation can upregulate target genes in a dominant, gain-of-function fashion. The differences between these two genotypes suggest that in select tissues the Mll-PTD requires cooperation with the Mll-WT in the genesis of the observed abnormality.
