Evidence map›Paper›PMID 28076791›Full record

ArticleCell reports2017

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 and 6 more

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cell reports, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
52citing papers in PubMed, 1 pooled it
4.1field-weighted citation impact, top 5% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

52 citing papers in PubMed, 1 synthesis or guideline pooled it, 91 citations in OpenAlex.

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  13. Aberrant stem cell and developmental programs in pediatric leukemia.Frontiers in cell and developmental biology · 2024
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

16 authors at 5 institutions in 2 countries.

Jon KerryMRC, Molecular Haematology Unit, NIHR Oxford Biomedical Research Centre Programme, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
Laura GodfreyMRC, Molecular Haematology Unit, NIHR Oxford Biomedical Research Centre Programme, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
Emmanouela RepapiComputational Biology Research Group, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
Marta TapiaMRC, Molecular Haematology Unit, NIHR Oxford Biomedical Research Centre Programme, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
Neil P BlackledgeLaboratory of Chromatin Biology and Transcription, Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK.
Helen MaDepartment of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Erica BallabioMRC, Molecular Haematology Unit, NIHR Oxford Biomedical Research Centre Programme, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
Sorcha O'ByrneDepartment of Paediatrics, University of Oxford, Children's Hospital, John Radcliffe, Oxford OX3 9DU, UK.
Frida PonthanWolfson Childhood Cancer Research Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne NE1 7RU, UK.
Olaf HeidenreichWolfson Childhood Cancer Research Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne NE1 7RU, UK.
Anindita RoyDepartment of Paediatrics, University of Oxford, Children's Hospital, John Radcliffe, Oxford OX3 9DU, UK.
Irene RobertsMRC, 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 KonoplevaDepartment of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Robert J KloseLaboratory of Chromatin Biology and Transcription, Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK.
Huimin GengDepartment of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
Thomas A MilneMRC, Molecular Haematology Unit, NIHR Oxford Biomedical Research Centre Programme, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK. Electronic address: thomas.milne@imm.ox.ac.uk.
University of Oxford · GBJohn Radcliffe Hospital · GBNewcastle University · GBThe University of Texas MD Anderson Cancer Center · USUniversity of California, San Francisco · US

Funding

Cancer Research UK 12788Cancer Research UK C27943/A12788Medical Research Council G0700089Medical Research Council MC_PC_15004Medical Research Council MC_UU_00016/13Medical Research Council MC_UU_00016/6Medical Research Council MC_UU_12009/14Medical Research Council MC_UU_12009/6Wellcome Trust 090532/Z/09/ZWellcome Trust 098024/Z/11/ZWellcome Trust 099175/Z/12/Z
6 · The paper itself

Abstract

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.

Indexed as

Binding SitesCell Line, TumorCpG IslandsDNA MethylationEnhancer Elements, GeneticGene Expression Regulation, LeukemicGenome, HumanHistone-Lysine N-MethyltransferaseHistonesHumansIntercellular Signaling Peptides and ProteinsLeukemiaLysineMethyltransferasesMyeloid-Lymphoid Leukemia ProteinOncogene Proteins, FusionDOT1L protein, humanHistone-Lysine N-MethyltransferaseHistonesIntercellular Signaling Peptides and Proteinslens epithelium-derived growth factorLysineMEN1 protein, humanMethyltransferasesMLL-AF4 fusion protein, humanMyeloid-Lymphoid Leukemia ProteinOncogene Proteins, FusionProto-Oncogene ProteinsDOT1Ldrug combination therapyepigenetic spreadingepigenetic therapyH3K79me2leukemiaMLLMLL-AF4

Identifiers

PMID28076791
PMCPMC5263239
OpenAlexW2567975067

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.