Homo-oligomerization of truncated transcription factors in human leukaemia
Section:
Section of Haemato-Oncology
Forced oligomerisation (formation of complexes with two or more identical subunits) has emerged as a powerful mechanism for unleashing the oncogenic properties of chimeric transcription factors in acute leukaemias (So and Cleary, 2004). 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 leukaemogenesis. Forced oligomerisation may alter the association of a DNA binding protein for its transcriptional cofactors, or the oligomerisation motifs themselves may constitutively recruit transcriptional effector molecules. Oligomerised 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 Oligomerised oncoprotein. Chimeric RARα and AML1 proteins induce constitutive repression following recruitment of co-repressors (So et al., 2000), whereas inappropriate maintenance of target gene expression by MLL chimeras may result from recruitment of co-activators or the basal transcriptional machinery (So et al., 2003b). To this end, we have recently demonstrated that disruption of aberrant of self-association ( Kwok et al., 2006 ) or intervention of RXR-mediated pathways ( Zeisig et al., 2007 ) in the oncogenic RARα fusion complexes can suppress transformation of primary hematopoietic cells.
We therefore hypothesize that molecular therapies directed at enzymatic activities of the aberrantly recruited cofactors, or antagonism of oligomerisation itself, can be novel therapeutic avenues of current and future investigation.
Our primary focuses:
- Study the roles of homo-oligomerisation in various chimeric transcription factors including RARα and Nup98 fusions involved in human leukaemias; and
- Characterize the transcriptional complexes recruited by MLL-oligomeric fusion proteins.
This work is supported by Cancer Research UK (CRUK) and Leukaemia Research Fund (LRF).
In the Section of Haemato-Oncology
