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Editorials
not possible when AF4-MLL is present. This could be a rational explanation for the observed clinical behavior of both groups of patients.
Another explanation could lie in the recent findings from Yokoyama’s laboratory.7,8 Okuda et al. elegantly showed that one of the functions of the pSer domain of the AF4 protein9 - which is fused to the N-terminus of MLL in the MLL-AF4 fusion protein - is recruitment of the SL1 complex. The SL1 complex is usually bound to RNA Pol I, which is present in the nucleolus and required for the transcription of rRNA genes. SL1 is artificially recruit- ed to MLL-AF4, but not to native MLL or AF4 complex- es.10 This powers up MLL-AF4 leading to a strong increase in gene transcription. The simple presence of the MLL- AF4 fusion protein causes a condition of severe stress, because it compromises protein biosynthesis, and cells may therefore easily display a phenotype of growth arrest or senescence.11 This is probably one of the reasons why it is so complicated to generate a true MLL-AF4 mouse model, and why so many laboratories have failed so far. With the exception of a recent study in which a hybrid between human MLL and mouse Af4 was used,12 no-one had been able to develop a satisfactory model
with only the human MLL-AF4 fusion. Since the sequences of the pSer domains of human and mouse AF4 differ slightly, it is very plausible that the human/mouse chimeric MLL-Af4 is unable to attract the SL1 component and thus does not impair protein biosynthesis. This needs to be tested in future experiments.
So, what is the precise role of AF4-MLL? AF4-MLL has been shown to strongly enhance gene transcription by overwriting the transcriptional elongation control.10,13 This massive increase in gene transcription (3- to 4-fold more mRNA) may help its molecular counterpart, MLL- AF4, to set the programming of its target genes, even under conditions of nucleolar stress (see Figure 1). In addi- tion, we have shown by ATAC sequencing in two inde- pendent cell lines that AF4-MLL strongly activates chro- matin in a very short time frame (unpublished data from our laboratory). The expression of AF4-MLL for 48 h was suf- ficient to open up the chromatin of all chromosomes apart from the centromeric regions and to massively increase gene transcription. Thus, the presence of AF4- MLL would allow the expression of any gene of interest, and increases the plasticity of the tumor cells. According to the data shown by Agraz-Doblas et al. this results in
Figure 1. Proposed fuctions of both t(4;11) fusion proteins. MLL-AF4 binds to Menin1/LEDGF and SL1 to target gene promotors and strongly activate gene transcrip- tion, while AF4-MLL overwrites transcriptional elongation control and strongly activates chromatin within a very short time window. Patients who express both fusions diplay HOXA gene signatures and have a better outcome, while patients who either do not express AF4-MLL or actively repress it, usually activate the homeobox pro- teins IRX1/2. Expression of both proteins has been correlated with a worse outcome (IRX1/2 strongly activate EGR1-3 and HOXB4).
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