Leukemia-associated ZMYND11-MBTD1 chimera induces leukemogenesis by hijacking TIP60 acetyltransferase and a PWWP-mediated chromatin association mechanism (ChIP-seq)

The recurring t(10;17)(p15;q21) chromosomal translocation as detected in a subset of human acute myeloid leukemia (AML) patients produces an aberrant fusion gene ZMYND11-MBTD1 (ZM), the biological consequence of which, however, remains elusive. Here we show that ZM chimera confers primary murine hematopoietic stem/progenitor cells (HSPCs) an indefinite self-renewal capability ex vivo and causes AML in vivo. Genomics analyses revealed that ZM directly binds to and maintains high expression of pro-leukemic transcription factor (TF) genes such as Hox, Meis1, Myc, Myb, and Sox4. Mechanistically, ZM interacts with and recruits the Tip60 acetyltransferase complex, both of which occupy promoter-proximal genomic regions that are enriched with histone acetylation and devoid of H3K27me3. Furthermore, systematic mutagenesis of ZM revealed an essential requirement of Tip60 association and an H3K36me3-binding PWWP domain for leukemic transformation and proto-oncogene activation. Finally, inhibitor of histone acetylation-‘reading’ bromodomain proteins is efficacious in treating ZM-induced AML. Collectively, this study demonstrated the AML-causing effect of ZM chimera with relevant animal models, examined into its gene-regulatory functions and protein interactome, and reports a promising mechanism-based therapeutic strategy. Mapping genome-wide binding sites of ZMYND1-MBTD1 (tagged with either 3XHA-3FLAG or GFP), Tip60 (tagged with GFP) and Brd4 in ZM-transformed murine AML cells. Genome-wide analysis of different histone modifications including H3K36me3, H3K27me3, H3K27ac, H4ac in ZM-transformed murine AML cells.