The partial tandem duplication of MLL (MLL-PJD) 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 M//-PTD in the absence of M//-WT. These M//PTD/∼ mice die at birth unlike the normal life expectancy of M//PTD/WT, M//WT/-, and M//WT/WT mice. Using M//W1™T fetal liver cells (FLC) as baseline, we compared Mllp™- with M//PTD/WT FLC and found both had increased HoxA gene expression and granulocyte-macrophage colony-forming progenitor cells (CFU-GM); in contrast, only M//PTD'WT FLC had increased pluripotent hemopoietic progenitors (CFU-GEMM). The similarities between M//PTD/WT and MIIPTD/- mice suggest that the M//-PTD mutation can upregulate target genes in a dominant, gainof-function fashion. The differences between these 2 genotypes suggest that in select tissues the Mll-PTD requires cooperation with the M/-WT in the genesis of the observed abnormality.