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Blood, 15 September 2008, Vol. 112, No. 6, pp. 2508-2511. Prepublished online as a Blood First Edition Paper on July 10, 2008; DOI 10.1182/blood-2008-01-134338.
NEOPLASIA The Mll partial tandem duplication: differential, tissue-specific activity in the presence or absence of the wild-type allele1 Department of Internal Medicine, Division of Hematology and Oncology; 2 Department of Veterinary Biosciences, and 3 Comprehensive Cancer Center–James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus The partial tandem duplication of MLL (MLL-PTD) is found in 5% to 10% of patients with acute myeloid leukemia (AML) and normal cytogenetics. Its expression in 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 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 granulocyte-macrophage colony-forming progenitor cells (CFU-GM); in contrast, only MllPTD/WT FLC had increased pluripotent hemopoietic progenitors (CFU-GEMM). The similarities between MllPTD/WT and MllPTD/– mice suggest that the Mll-PTD mutation can up-regulate target genes in a dominant, gain-of-function fashion. The differences between these 2 genotypes suggest that in select tissues the Mll-PTD requires cooperation with the Mll-WT in the genesis of the observed abnormality.
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