Oncogenic ZMYND11-MBTD1 fusion protein anchors the NuA4/TIP60 histone acetyltransferase complex to the coding region of active genes
Maëva Devoucoux,
Victoire Fort,
Gabriel Khelifi,
Joshua Xu,
Nader Alerasool,
Maxime Galloy,
Nicholas Wong,
Gaëlle Bourriquen,
Amelie Fradet-Turcotte,
Mikko Taipale,
Kristin Hope,
Samer M.I. Hussein,
Jacques Côté
Affiliations
Maëva Devoucoux
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
Victoire Fort
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
Gabriel Khelifi
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
Joshua Xu
Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada
Nader Alerasool
Donnelly Centre for Cellular and Biomolecular Research, Department of Molecular Genetics, University of Toronto, Toronto ON, Canada
Maxime Galloy
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
Nicholas Wong
Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
Gaëlle Bourriquen
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
Amelie Fradet-Turcotte
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
Mikko Taipale
Donnelly Centre for Cellular and Biomolecular Research, Department of Molecular Genetics, University of Toronto, Toronto ON, Canada
Kristin Hope
Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
Samer M.I. Hussein
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; Corresponding author
Jacques Côté
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; Corresponding author
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.
