Perspective Dimerization: a versatile switch for oncogenesis

Forced dimerization or oligomerization has emerged as a powerful mechanism for un-leashing the oncogenic properties of chi-meric transcription factors in acute leuke-mias. Fusion of transcriptional regulators with a variety of heterologous partner pro-teins as a consequence of chromosomal rearrangements induces inappropriate self-association, leading to aberrant transcrip-tional properties and leukemogenesis. Forced dimerization/oligomerization may alter the association of a DNA-binding protein for its transcriptional cofactors, or the dimerization motifs themselves may constitutively recruit transcriptional effec-tor molecules. Oligomerized chimeras may also sequester essential partners or cofactors to exert dominant-negative ef-fects on target gene expression. A key mechanistic feature, and one with major clinical implications, is the nature of the transcriptional cofactors that are recruited by the dimerized oncoprotein. Chimeric RAR and acute myeloid leukemia 1 (AML1) proteins induce constitutive re-pression after the recruitment of corepres-sors, whereas inappropriate maintenance of target gene expression by mixed-lineage leukemia (MLL) chimeras may re-sult from the recruitment of coactivators or the basal transcriptional machinery. Molecular therapies directed at enzy-matic activities of the aberrantly recruited cofactors, or antagonism of dimerization itself, represent promising avenues of current and future investigation. (Blood