Acute myeloid leukemias (AMLs) are consistently associated with chromosomal rearrangements that result in the generation of chimeric genes and fusion proteins. One of the two affected genes is frequently a transcription factor Involved in the regulation of hematopoletic differentiation. Recent findings suggest a common leukemogenic mechanism for the fused transcription factor: abnormal recruitment of histone deacetylase (HDAC)-containing complexes to its target promoters. Inhibition of HDAC enzymatic activity reverts the leukemic phenotype in vitro and therefore represents a plausible strategy for antileukemic therapy. In this review, we first briefly describe the molecular structure and mechanisms of the most frequent AML associated fusion proteins (RAR, MLL, and CBF fusions) and then summarize available knowledge about their effects on the nuclear architecture. We propose that alteration of nuclear compartmentalization might represent an additional common mechanism of leukemogenesis.