After DNA replication, sister chromatids must be untangled, or decatenated, 
before mitosis so that chromatids do not tear during anaphase. Topoisomerase 
IIalpha (Topo IIalpha) is the major decatenating enzyme. Topo IIalpha inhibitors 
prevent decatenation, causing cells to arrest during mitosis. Here we report 
that acute myeloid leukemia cells fail to arrest at the mitotic decatenation 
checkpoint, and their progression through this checkpoint is regulated by the 
DNA repair component Metnase (also termed SETMAR). Metnase contains a SET 
histone methylase and transposase nuclease domain, and is a component of the 
nonhomologous end-joining DNA double-strand break repair pathway. Metnase 
interacts with Topo IIalpha and enhances its decatenation activity. Here we show 
that multiple types of acute leukemia cells have an attenuated mitotic arrest 
when decatenation is inhibited and that in an acute myeloid leukemia (AML) cell 
line this is mediated by Metnase. Of further importance, Metnase permits 
continued proliferation of these AML cells even in the presence of the clinical 
Topo IIalpha inhibitor VP-16. In vitro, purified Metnase prevents VP-16 
inhibition of Topo IIalpha decatenation of tangled DNA. Thus, Metnase expression 
levels may predict AML resistance to Topo IIalpha inhibitors, and Metnase is a 
potential therapeutic target for small molecule interference.