Tip60 activates Hoxa9 and Meis1 expression through acetylation of H2A.Z, promoting MLL-AF10 and MLL-ENL acute myeloid leukemia

Chromosome translocations involving the MLL gene are common rearrangements in leukemia. Such translocations fuse the MLL 5'-region to partner genes in frame, producing MLL-fusions that cause MLL-related leukemia. MLL-fusions activate transcription of target genes such as HoxA cluster and Meis1, but the underlying mechanisms remain to be fully elucidated. In this study, we discovered that Tip60, a MYST-type histone acetyltransferase, was required for the expression of HoxA cluster and Meis1 genes and the development of MLL-fusion leukemia. Tip60 was recruited by MLL-AF10 and MLL-ENL fusions to the Hoxa9 locus, where it acetylated H2A.Z, thereby promoting Hoxa9 gene expression. Conditional deletion of Tip60 prevented the development of MLL-AF10 and MLL-ENL leukemia, indicating that Tip60 is indispensable for the leukemogenic activity of the MLL-AF10 and MLL-ENL-fusions. Our findings provide novel insight about epigenetic regulation in the development of MLL-AF10 and MLL-ENL-fusion leukemia.

Automated summary

This study revealed that the MYST-type histone acetyltransferase, Tip60, is required for the expression of HoxA cluster and Meis1 genes and the development of MLL fusion leukemia. Tip60 is recruited by MLL-AF10 and MLL-ENL fusions to certain gene loci, where it promotes gene expression, and its conditional deletion prevents the development of MLL fusion leukemia, highlighting the importance of Tip60 in leukemogenesis associated with MLL fusions.