Cell fate depends on the interplay between chromatin regulators and 
transcription factors. Here we show that activity of the Mi-2β 
nucleosome-remodeling and histone-deacetylase (NuRD) complex was controlled by 
the Ikaros family of lymphoid lineage-determining proteins. Ikaros, an integral 
component of the NuRD complex in lymphocytes, tethered this complex to active 
genes encoding molecules involved in lymphoid differentiation. Loss of Ikaros 
DNA-binding activity caused a local increase in chromatin remodeling and histone 
deacetylation and suppression of lymphoid cell-specific gene expression. Without 
Ikaros, the NuRD complex also redistributed to transcriptionally poised genes 
that were not targets of Ikaros (encoding molecules involved in proliferation 
and metabolism), which induced their reactivation. Thus, release of NuRD from 
Ikaros regulation blocks lymphocyte maturation and mediates progression to a 
leukemic state by engaging functionally opposing epigenetic and genetic 
networks.