Biomedical Engineering Reference
In-Depth Information
Accordingly, the revised model of APL pathogenesis postulates that
PML/RARα is a potent gain-of-function mutant that performs many
tasks that neither translocation partner does alone [55].
10.2.3.1 Global transcriptional repression
PML/RARα behaves as a potent repressor of the RA signalling
pathway (Fig. 10.1). The traditional model postulated that PML/
RARα acted as a constitutive transcriptional repressor that altered
the normal RARα signalling in APL cells, as the chimeric protein
is unable to respond to physiological fluctuations of RA [42]. The
transcriptional repression was shown to be the consequence of
greatly enhanced binding to the SMRT/NCoR co-repressors and
HDACs [23]. PML/RARα homodimerises and binds to DNA at the
RARE sites even in the absence of its normal heterodimeric partner
RXR. The homodimerisation is thought to enhance the binding of
the physiological RARα interactors. Simplistically, enhanced co-
repressors binding depends upon the fact that the homodimer
harbours two co-repressor docking sites and not just one as in RXR/
RARα heterodimer, leading to a change in stoichiometry of association
of PML/RARα with co-repressors and chromatin modifiers [39].
However, in addition, the formation of homodimers leads to the
creation of novel binding interfaces. Histone methyltransferase
SUV39H1, responsible for trimethylation of lysine 9 of histone H3
is one of the chimera-specific partners responsible for imposing a
heterochromatin-like structure on target genes, thereby establishing
permanent transcriptional silencing [9]. Similarly, polycomb
repressive complex 2 (PRC2) represents another example of a new
PML/RARα interactor. It has been found that PRC2 is recruited to
tumour suppressor genes causing and maintaining their silencing
during the initial steps of PML/RARα driven leukaemogenesis [57].
In the current model, the transcriptional repression is not
restricted to the RARα target genes but the epigenetic regulation is
extended to areas of the genome that do not possess the classical
DR2 and DR5 repeats in their promoter. Recent genome-wide
studies have shown that PML/RARα binds to regions containing
atypical DR1, DR3, DR4 motifs, as well as, sites with other spacing
and orientation [31]. It is thought that this massively enhanced DNA
binding is underscored by the formation of heterotetramers (PML/
RARα-RXRα)x2 giving rise to a complex with four DNA binding
