MLL-AF4 Spreading Identifies Binding Sites that Are Distinct from Super-Enhancers and that Govern Sensitivity to DOT1L Inhibition in Leukemia
Jon Kerry,
Laura Godfrey,
Emmanouela Repapi,
Marta Tapia,
Neil P. Blackledge,
Helen Ma,
Erica Ballabio,
Sorcha O’Byrne,
Frida Ponthan,
Olaf Heidenreich,
Anindita Roy,
Irene Roberts,
Marina Konopleva,
Robert J. Klose,
Huimin Geng,
Thomas A. Milne
Affiliations
Jon Kerry
MRC, Molecular Haematology Unit, NIHR Oxford Biomedical Research Centre Programme, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK
Laura Godfrey
MRC, Molecular Haematology Unit, NIHR Oxford Biomedical Research Centre Programme, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK
Emmanouela Repapi
Computational Biology Research Group, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK
Marta Tapia
MRC, Molecular Haematology Unit, NIHR Oxford Biomedical Research Centre Programme, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK
Neil P. Blackledge
Laboratory of Chromatin Biology and Transcription, Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK
Helen Ma
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Erica Ballabio
MRC, Molecular Haematology Unit, NIHR Oxford Biomedical Research Centre Programme, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK
Sorcha O’Byrne
Department of Paediatrics, University of Oxford, Children’s Hospital, John Radcliffe, Oxford OX3 9DU, UK
Frida Ponthan
Wolfson Childhood Cancer Research Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne NE1 7RU, UK
Olaf Heidenreich
Wolfson Childhood Cancer Research Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne NE1 7RU, UK
Anindita Roy
Department of Paediatrics, University of Oxford, Children’s Hospital, John Radcliffe, Oxford OX3 9DU, UK
Irene Roberts
MRC, Molecular Haematology Unit, NIHR Oxford Biomedical Research Centre Programme, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK; Department of Paediatrics, University of Oxford, Children’s Hospital, John Radcliffe, Oxford OX3 9DU, UK
Marina Konopleva
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Robert J. Klose
Laboratory of Chromatin Biology and Transcription, Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK
Huimin Geng
Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
Thomas A. Milne
MRC, Molecular Haematology Unit, NIHR Oxford Biomedical Research Centre Programme, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK; Corresponding author
Summary: Understanding the underlying molecular mechanisms of defined cancers is crucial for effective personalized therapies. Translocations of the mixed-lineage leukemia (MLL) gene produce fusion proteins such as MLL-AF4 that disrupt epigenetic pathways and cause poor-prognosis leukemias. Here, we find that at a subset of gene targets, MLL-AF4 binding spreads into the gene body and is associated with the spreading of Menin binding, increased transcription, increased H3K79 methylation (H3K79me2/3), a disruption of normal H3K36me3 patterns, and unmethylated CpG regions in the gene body. Compared to other H3K79me2/3 marked genes, MLL-AF4 spreading gene expression is downregulated by inhibitors of the H3K79 methyltransferase DOT1L. This sensitivity mediates synergistic interactions with additional targeted drug treatments. Therefore, epigenetic spreading and enhanced susceptibility to epidrugs provides a potential marker for better understanding combination therapies in humans. : Translocations of the MLL gene produce fusion proteins such as MLL-AF4 that cause poor-prognosis leukemias. Kerry et al. show that MLL-AF4 can spread into the gene body of some target genes. Spreading targets have an aberrant chromatin signature and are sensitive to DOT1L inhibitors. Keywords: MLL, MLL-AF4, DOT1L, H3K79me2, leukemia, epigenetic therapy, drug combination therapy, epigenetic spreading
