Abstract
Recurring chromosomal translocation t(10;17)(p15;q21) present in a subset of human acute myeloid leukemia (AML) patients creates an aberrant fusion gene termed ZMYND11-MBTD1 (ZM); however, its function remains undetermined. Here, we show that ZM confers primary murine hematopoietic stem/progenitor cells indefinite self-renewal capability ex vivo and causes AML in vivo. Genomics profilings reveal that ZM directly binds to and maintains high expression of pro-leukemic genes including Hoxa, Meis1, Myb, Myc and Sox4. Mechanistically, ZM recruits the NuA4/Tip60 histone acetyltransferase complex to cis-regulatory elements, sustaining an active chromatin state enriched in histone acetylation and devoid of repressive histone marks. Systematic mutagenesis of ZM demonstrates essential requirements of Tip60 interaction and an H3K36me3-binding PWWP (Pro-Trp-Trp-Pro) domain for oncogenesis. Inhibitor of histone acetylation-'reading' bromodomain proteins, which act downstream of ZM, is efficacious in treating ZM-induced AML. Collectively, this study demonstrates AML-causing effects of ZM, examines its gene-regulatory roles, and reports an attractive mechanism-guided therapeutic strategy.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylation
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Animals
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Carcinogenesis
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Cell Cycle Proteins / chemistry*
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Cell Cycle Proteins / metabolism*
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Cell Differentiation
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Cell Proliferation
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Cell Transformation, Neoplastic
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Chromatin / metabolism*
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Chromosomal Proteins, Non-Histone / chemistry*
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Chromosomal Proteins, Non-Histone / metabolism*
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Co-Repressor Proteins / chemistry*
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Co-Repressor Proteins / metabolism*
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DNA-Binding Proteins / chemistry*
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DNA-Binding Proteins / metabolism*
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Disease Models, Animal
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Enhancer Elements, Genetic / genetics
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Gene Expression Regulation, Leukemic
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Genome, Human
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HEK293 Cells
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Hematopoietic Stem Cells / metabolism
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Histones / metabolism
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Humans
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Leukemia, Myeloid, Acute / genetics
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Leukemia, Myeloid, Acute / pathology*
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Lysine Acetyltransferase 5 / metabolism*
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Mice
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Mice, Inbred BALB C
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Neoplastic Stem Cells / metabolism
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Neoplastic Stem Cells / pathology
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Oncogene Proteins, Fusion / metabolism
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Protein Binding
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Protein Domains
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Transcription Factors / metabolism
Substances
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BRD4 protein, human
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Cell Cycle Proteins
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Chromatin
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Chromosomal Proteins, Non-Histone
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Co-Repressor Proteins
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DNA-Binding Proteins
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Histones
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MBTD1 protein, human
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Oncogene Proteins, Fusion
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Transcription Factors
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ZMYND11 protein, human
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KAT5 protein, human
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Lysine Acetyltransferase 5