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Blood, 15 August 2004, Vol. 104, No. 4, pp. 919-922.
Prepublished online as a Blood First Edition Paper on May 6, 2004; DOI 10.1182/blood-2004-03-0992.
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Submitted March 17, 2004
Accepted April 17, 2004
Dimerization: A versatile switch for oncogenesis
Chi Wai So* and Michael L Cleary
Pathology, Stanford University School of Medicine, Stanford, CA, USA
* Corresponding author; email: cwso{at}stanford.edu.
Forced dimerization or oligomerization has emerged as a powerful mechanism for unleashing the oncogenic properties of chimeric transcription factors in acute leukemias. Fusion of transcriptional regulators with a variety of heterologous partner proteins as a consequence of chromosomal rearrangements induces inappropriate self-association leading to aberrant transcriptional 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 effector molecules. Oligomerized chimeras may also sequester essential partners or cofactors to exert dominant-negative effects 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 AML1 proteins induce constitutive repression following recruitment of co-repressors, whereas inappropriate maintenance of target gene expression by MLL chimeras may result from recruitment of co-activators or the basal transcriptional machinery. Molecular therapies directed at enzymatic activities of the aberrantly recruited cofactors, or antagonism of dimerization itself, represent promising avenues of current and future investigation.
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