An alternative splice process renders MLL either into an transcriptional activator or repressor

We analyzed the biological properties of the MLL PHD1 – 3 domain. This domain is encoded by MLL exons 11 – 16 and localizes next to the Bromo-domain (MLL exons 17 – 19). We have identified 4 different splice variants that alter functions of the PHD domain 3, in particular its dimerization capacity and binding to CYP33 or H3K4_me3. Binding to CYP33 allows to complex with BMI1, CBX4, HDAC and KDM 5B, and thus, to repress transcriptional processes. One out of 4 splice variants was able to bind CYP33, while others allow binding to H3K4me3 which in turn will enhance transcription. Of interest, MLL exon 11 encodes part of the PHD1 domain. Therefore, leukemia patients with chromosomal breakpoints in MLL intron 9 or 10 exhibit an intact PHD1 – 3 domain, while chromosomal breakpoints in MLL intron 11 always result in a disrupted PHD domain. Thus, the position of chromosomal breakpoints in MLL-r leukemia patients is of importance as it impacts on the resulting properties of the MLL fusion proteins.

This work is supported by grant Ma 1876/10 – 1 from the Deutsche Forschungsgemeinschaft.