Transcriptomics

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


ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE150424 | GEO | 2021/01/14

REPOSITORIES: GEO

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