Oncogenic mechanisms mediated by MLL oncoproteins
Section:
Section of Haemato-Oncology
The Mixed Lineage Leukaemia gene (MLL) in chromosomal 11q23 encoding a H3K4 histone methyltransferase is a frequent target by chromosomal translocation in human acute leukaemia. As a result of gene rearrangement, MLL can fuse with more than 40 different translocation partners to form in-frame chimeric oncoproteins. We and others have previously proposed two major oncogenic activation mechanisms of MLL: 1) direct fusion with transcriptional activation domain (So and Cleary, 2002; So and Cleary, 2003); and 2) forced homo-oligomerisation of truncated MLL as a result of acquisition of self-association domain from fusion partners (So and Cleary, 2004; So et al., 2003b). Both mechanisms will lead to constitutive activation of MLL downstream targets such as Hox genes, which is critical for MLL-mediated transformation (So et al., 2004). To this end, we have recently identified a hostone methyltransferase, PRMT1 as an essential component for an MLL oncogenic complex ( Cheung et al., 2007 ). Targeting PRMT1 is sufficient to suppress MLL-EEN mediated transformation. This finding also provides the first experimental evidence linking protein arginine methyltransferases to human cancer. Thus we hypothesise that aberrant recruitment of transcription activation machinery to downstream targets of MLL fusion proteins is key for MLL-mediated leukaemogenesis, which may also represent a promising avenue for cancer therapeutics.
Our primary focuses:
- Characterize the transcriptional machinery hijacked by MLL chimeric fusion proteins;
- Identify critical downstream targets of MLL fusion proteins; and
- Investigate the roles of histone methyltransferase in MLL-mediated leukaemia.
This work is supported by Association of International Cancer Research (AICR).
In the Section of Haemato-Oncology
