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

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 d...

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Autores principales: Mas, Glòria, Santoro, Fabio, Blanco, Enrique, Gamarra Figueroa, Gianni Paolo, Le Dily, François, Frigè, Gianmaria, Vidal, Enrique, Mugianesi, Francesca, Ballaré, Cecilia, Gutierrez, Arantxa, Sparavier, Aleksandra, Marti-Renom, Marc A., Minucci, Saverio, Di Croce, Luciano
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9067408/
https://www.ncbi.nlm.nih.gov/pubmed/35450883
http://dx.doi.org/10.1101/gad.349115.121
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author Mas, Glòria
Santoro, Fabio
Blanco, Enrique
Gamarra Figueroa, Gianni Paolo
Le Dily, François
Frigè, Gianmaria
Vidal, Enrique
Mugianesi, Francesca
Ballaré, Cecilia
Gutierrez, Arantxa
Sparavier, Aleksandra
Marti-Renom, Marc A.
Minucci, Saverio
Di Croce, Luciano
author_facet Mas, Glòria
Santoro, Fabio
Blanco, Enrique
Gamarra Figueroa, Gianni Paolo
Le Dily, François
Frigè, Gianmaria
Vidal, Enrique
Mugianesi, Francesca
Ballaré, Cecilia
Gutierrez, Arantxa
Sparavier, Aleksandra
Marti-Renom, Marc A.
Minucci, Saverio
Di Croce, Luciano
author_sort Mas, Glòria
collection PubMed
description 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.
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spelling pubmed-90674082022-10-01 In vivo temporal resolution of acute promyelocytic leukemia progression reveals a role of Klf4 in suppressing early leukemic transformation Mas, Glòria Santoro, Fabio Blanco, Enrique Gamarra Figueroa, Gianni Paolo Le Dily, François Frigè, Gianmaria Vidal, Enrique Mugianesi, Francesca Ballaré, Cecilia Gutierrez, Arantxa Sparavier, Aleksandra Marti-Renom, Marc A. Minucci, Saverio Di Croce, Luciano Genes Dev Research Paper 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. Cold Spring Harbor Laboratory Press 2022-04-01 /pmc/articles/PMC9067408/ /pubmed/35450883 http://dx.doi.org/10.1101/gad.349115.121 Text en © 2022 Mas et al.; Published by Cold Spring Harbor Laboratory Press https://creativecommons.org/licenses/by-nc/4.0/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/ (https://creativecommons.org/licenses/by-nc/4.0/) .
spellingShingle Research Paper
Mas, Glòria
Santoro, Fabio
Blanco, Enrique
Gamarra Figueroa, Gianni Paolo
Le Dily, François
Frigè, Gianmaria
Vidal, Enrique
Mugianesi, Francesca
Ballaré, Cecilia
Gutierrez, Arantxa
Sparavier, Aleksandra
Marti-Renom, Marc A.
Minucci, Saverio
Di Croce, Luciano
In vivo temporal resolution of acute promyelocytic leukemia progression reveals a role of Klf4 in suppressing early leukemic transformation
title In vivo temporal resolution of acute promyelocytic leukemia progression reveals a role of Klf4 in suppressing early leukemic transformation
title_full In vivo temporal resolution of acute promyelocytic leukemia progression reveals a role of Klf4 in suppressing early leukemic transformation
title_fullStr In vivo temporal resolution of acute promyelocytic leukemia progression reveals a role of Klf4 in suppressing early leukemic transformation
title_full_unstemmed In vivo temporal resolution of acute promyelocytic leukemia progression reveals a role of Klf4 in suppressing early leukemic transformation
title_short In vivo temporal resolution of acute promyelocytic leukemia progression reveals a role of Klf4 in suppressing early leukemic transformation
title_sort in vivo temporal resolution of acute promyelocytic leukemia progression reveals a role of klf4 in suppressing early leukemic transformation
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9067408/
https://www.ncbi.nlm.nih.gov/pubmed/35450883
http://dx.doi.org/10.1101/gad.349115.121
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