Oncogenic ZMYND11-MBTD1 fusion protein anchors the NuA4/TIP60 histone acetyltransferase complex to the coding region of active genes

Cell Reports

Nader Alerasool¹  Jacques Côté²  Kristin Hope³  Maxime Galloy³  Samer M.I. Hussein⁴  Gaëlle Bourriquen⁴  Joshua Xu⁴  Nicholas Wong⁵  Amelie Fradet-Turcotte⁵  Gabriel Khelifi⁵  Mikko Taipale⁵  Victoire Fort⁵  Maëva Devoucoux⁵ 

[1] Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada;Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada;Donnelly Centre for Cellular and Biomolecular Research, Department of Molecular Genetics, University of Toronto, Toronto ON, Canada;Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada;St. Patrick Research Group in Basic Oncology, Laval University Cancer Research Center, Oncology Division of CHU de Québec-Université Laval Research Center, Quebec City, QC G1R 3S3, Canada;

关键词: ZMYND11;    MBTD1;    NuA4;    TIP60;    AML;    translocation;   

DOI  :  

来源: DOAJ

【 摘 要 】

Summary: A recurrent chromosomal translocation found in acute myeloid leukemia leads to an in-frame fusion of the transcription repressor ZMYND11 to MBTD1, a subunit of the NuA4/TIP60 histone acetyltransferase complex. To understand the abnormal molecular events that ZMYND11-MBTD1 expression can create, we perform a biochemical and functional characterization comparison to each individual fusion partner. ZMYND11-MBTD1 is stably incorporated into the endogenous NuA4/TIP60 complex, leading to its mislocalization on the body of genes normally bound by ZMYND11. This can be correlated to increased chromatin acetylation and altered gene transcription, most notably on the MYC oncogene, and alternative splicing. Importantly, ZMYND11-MBTD1 expression favors Myc-driven pluripotency during embryonic stem cell differentiation and self-renewal of hematopoietic stem/progenitor cells. Altogether, these results indicate that the ZMYND11-MBTD1 fusion functions primarily by mistargeting the NuA4/TIP60 complex to the body of genes, altering normal transcription of specific genes, likely driving oncogenesis in part through the Myc regulatory network.

【 授权许可】

Unknown