The ETO2 transcriptional cofactor maintains acute leukemia by driving a MYB/EP300‐dependent stemness program

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dc.contributor.authorFagnan, Alexandre
dc.contributor.authorAnguita Mandly, Eduardo Luis
dc.contributor.authorMercher, Thomas
dc.date.accessioned2024-07-02T08:51:25Z
dc.date.available2024-07-02T08:51:25Z
dc.date.issued2024-06
dc.description.abstractTranscriptional cofactors of the ETO family are recurrent fusion partners in acute leukemia. We characterized the ETO2 regulome by integrating transcriptomic and chromatin binding analyses in human erythroleukemia xenografts and controlled ETO2 depletion models. We demonstrate that beyond its well‐established repressive activity, ETO2 directly activates transcription of MYB, among other genes. The ETO2‐activated signature is associated with a poorer prognosis in erythroleukemia but also in other acute myeloid and lymphoid leukemia subtypes. Mechanistically, ETO2 colocalizes with EP300 and MYB at enhancers supporting the existence of an ETO2/MYB feedforward transcription activation loop (e.g., on MYB itself). Both small‐molecule and PROTAC‐mediated inhibition of EP300 acetyltransferases strongly reduced ETO2 protein, chromatin binding, and ETO2‐activated transcripts. Taken together, our data show that ETO2 positively enforces a leukemia maintenance program that is mediated in part by the MYB transcription factor and that relies on acetyltransferase cofactors to stabilize ETO2 scaffolding activity.
dc.description.departmentDepto. de Medicina
dc.description.facultyFac. de Medicina
dc.description.refereedTRUE
dc.description.statuspub
dc.identifier.citationFagnan A, Aid Z, Baille M, Drakul A, Robert E, Lopez CK, Thirant C, Lecluse Y, Rivière J, Ignacimouttou C, Salmoiraghi S, Anguita E, Naimo A, Marzac C, Pflumio F, Malinge S, Wichmann C, Huang Y, Lobry C, Chaumeil J, Soler E, Bourquin JP, Nerlov C, Bernard OA, Schwaller J, Mercher T. The ETO2 transcriptional cofactor maintains acute leukemia by driving a MYB/EP300-dependent stemness program. Hemasphere. 2024 Jun 19;8(6):e90. doi: 10.1002/hem3.90. PMID: 38903535; PMCID: PMC11187848.
dc.identifier.doi10.1002/hem3.90
dc.identifier.issn2572-9241
dc.identifier.issn2572-9241
dc.identifier.officialurlhttps://doi.org/10.1002/hem3.90
dc.identifier.urihttps://hdl.handle.net/20.500.14352/105429
dc.issue.number6
dc.journal.titleHemasphere
dc.language.isoeng
dc.page.initiale90
dc.publisherWiley
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 Internationalen
dc.rights.accessRightsopen access
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject.cdu616.15
dc.subject.cdu616.155.392-036.11
dc.subject.keywordHematología
dc.subject.keywordLeucemia aguda
dc.subject.ucmHematología
dc.subject.unesco3205.04 Hematología
dc.subject.unesco2407 Biología Celular
dc.subject.unesco2415 Biología Molecular
dc.titleThe ETO2 transcriptional cofactor maintains acute leukemia by driving a MYB/EP300‐dependent stemness program
dc.typejournal article
dc.type.hasVersionVoR
dc.volume.number8
dspace.entity.typePublication
relation.isAuthorOfPublicationaa41c8cb-98ce-401a-99fb-32d3a2f96f00
relation.isAuthorOfPublication.latestForDiscoveryaa41c8cb-98ce-401a-99fb-32d3a2f96f00
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