In vivo temporal resolution of acute promyelocytic leukemia progression reveals a role of Klf4 in suppressing early leukemic transformation

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  • dc.contributor.author Mas, Glòria
  • dc.contributor.author Santoro, Fabio
  • dc.contributor.author Blanco, Enrique
  • dc.contributor.author Gamarra Figueroa, Gianni Paolo
  • dc.contributor.author Le Dily, François
  • dc.contributor.author Frigè, Gianmaria
  • dc.contributor.author Vidal, Enrique
  • dc.contributor.author Mugianesi, Francesca
  • dc.contributor.author Ballaré, Cecilia Julia
  • dc.contributor.author Gutiérrez, Arantxa
  • dc.contributor.author Sparavier, Aleksandra
  • dc.contributor.author Marti-Renom, Marc A.
  • dc.contributor.author Minucci, Saverio
  • dc.contributor.author Di Croce, Luciano
  • dc.date.accessioned 2022-05-12T07:41:57Z
  • dc.date.available 2022-05-12T07:41:57Z
  • dc.date.issued 2022
  • dc.description.abstract Genome organization plays a pivotal role in transcription, but how transcription factors (TFs) rewire the structure of the genome to initiate and maintain the programs that lead to oncogenic transformation remains poorly understood. Acute promyelocytic leukemia (APL) is a fatal subtype of leukemia driven by a chromosomal translocation between the promyelocytic leukemia (PML) and retinoic acid receptor α (RARα) genes. We used primary hematopoietic stem and progenitor cells (HSPCs) and leukemic blasts that express the fusion protein PML-RARα as a paradigm to temporally dissect the dynamic changes in the epigenome, transcriptome, and genome architecture induced during oncogenic transformation. We found that PML-RARα initiates a continuum of topologic alterations, including switches from A to B compartments, transcriptional repression, loss of active histone marks, and gain of repressive histone marks. Our multiomics-integrated analysis identifies Klf4 as an early down-regulated gene in PML-RARα-driven leukemogenesis. Furthermore, we characterized the dynamic alterations in the Klf4 cis-regulatory network during APL progression and demonstrated that ectopic Klf4 overexpression can suppress self-renewal and reverse the differentiation block induced by PML-RARα. Our study provides a comprehensive in vivo temporal dissection of the epigenomic and topological reprogramming induced by an oncogenic TF and illustrates how topological architecture can be used to identify new drivers of malignant transformation.
  • dc.description.sponsorship Funding: G.M. conducted this work with support from “Becas Leonardo a Investigadores y Creadores Culturales” from the Banco Bilbao Vizcaya Argentaria Foundation. The work in the Di Croce laboratory is supported by grants from the Spanish Ministry of Science and Innovation (PID2019-108322GB-100), “Fundación Vencer El Cancer” (VEC), the European Regional Development Fund (ERDF), Secretaria d'Universitats i Recerca del Departament d'Economia I Coneixement de la Generalitat de Catalunya (Programa Operatiu FEDER de Catalunya 2014-2020; AGAUR, 2017 SGR and 2019 FI_B 00426), the European Union's Horizon 2020 research and innovation programme under Marie Skłodowska-Curie grant agreement number 713673 “ChromDesign,” and the Fondo Social Europeo (FSE). A.S. is supported by a fellowship from “la Caixa” Foundation (ID 100010434). The work was partially supported by awards from the European Research Council under the 7th Framework Program (FP7/2007-2013 609989), the European Union's Horizon 2020 Research and Innovation Program (676556), and the Spanish Ministerio de Ciencia, Innovación y Universidades (BFU2017-85926-P) to M.A.M.-R. We acknowledge support of the Spanish Ministry of Science and Innovation through the Instituto de Salud Carlos III, the EMBL partnership, and the cofinancing with funds from the European Regional Development Fund (FEDER), Centro de Excelencia Severo Ochoa; Centres de Recerca de Catalunya Programme/Generalitat de Catalunya
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Mas G, Santoro F, Blanco E, Gamarra Figueroa GP, Le Dily F, Frigè G et al. In vivo temporal resolution of acute promyelocytic leukemia progression reveals a role of Klf4 in suppressing early leukemic transformation. Genes Dev. 2022 Apr 1;36(7-8):451-467. DOI:10.1101/gad.349115.121
  • dc.identifier.doi http://dx.doi.org/10.1101/gad.349115.121
  • dc.identifier.issn 1549-5477
  • dc.identifier.uri http://hdl.handle.net/10230/53063
  • dc.language.iso eng
  • dc.publisher Cold Spring Harbor Laboratory Press (CSHL Press)
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/713673
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/676556
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/609989
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/BFU2017-85926-P
  • dc.rights © 2022 Mas et al. This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.subject.other Leucèmia
  • dc.subject.other Genòmica
  • dc.subject.other Cromatina
  • dc.title In vivo temporal resolution of acute promyelocytic leukemia progression reveals a role of Klf4 in suppressing early leukemic transformation
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/acceptedVersion

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