ZMYND11-MBTD1 induces leukemogenesis through hijacking NuA4/TIP60 acetyltransferase complex and a PWWP-mediated chromatin association mechanism

Nat Commun. 2021 Feb 16;12(1):1045. doi: 10.1038/s41467-021-21357-3.

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

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Animals
  • Carcinogenesis
  • Cell Cycle Proteins / chemistry*
  • Cell Cycle Proteins / metabolism*
  • Cell Differentiation
  • Cell Proliferation
  • Cell Transformation, Neoplastic
  • Chromatin / metabolism*
  • Chromosomal Proteins, Non-Histone / chemistry*
  • Chromosomal Proteins, Non-Histone / metabolism*
  • Co-Repressor Proteins / chemistry*
  • Co-Repressor Proteins / metabolism*
  • DNA-Binding Proteins / chemistry*
  • DNA-Binding Proteins / metabolism*
  • Disease Models, Animal
  • Enhancer Elements, Genetic / genetics
  • Gene Expression Regulation, Leukemic
  • Genome, Human
  • HEK293 Cells
  • Hematopoietic Stem Cells / metabolism
  • Histones / metabolism
  • Humans
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / pathology*
  • Lysine Acetyltransferase 5 / metabolism*
  • Mice, Inbred BALB C
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology
  • Oncogene Proteins, Fusion / metabolism
  • Protein Binding
  • Protein Domains
  • Transcription Factors / metabolism

Substances

  • BRD4 protein, human
  • Cell Cycle Proteins
  • Chromatin
  • Chromosomal Proteins, Non-Histone
  • Co-Repressor Proteins
  • DNA-Binding Proteins
  • Histones
  • MBTD1 protein, human
  • Oncogene Proteins, Fusion
  • Transcription Factors
  • ZMYND11 protein, human
  • KAT5 protein, human
  • Lysine Acetyltransferase 5