Inhibition of class I HDACs abrogates the dominant effect of MLL-AF4 by activation of wildtype MLL

The ALOX5 gene encodes 5-lipoxygenase (5-LO), a key enzyme of inflammatory reactions. 5-LO expression is induced by VitD3 and/or TGFβ and transcription initiation was associated with an increase in histone H3 lysine 4 trimethylation (H3K4me3) in a TSA-inducible fashion. Therefore, we investigated the effects of the MLL protein and its derivatives, MLL-AF4 and AF4-MLL, respectively. MLL-AF4 was able to enhance ALOX5 promoter activity by 47-fold which was further stimulated when either VDR/RXR or SMAD3/SMAD4 were co-transfected. Additionally, we investigated several HDAC inhibitors in combination with gene knockdo…