Human iPSCs-based modeling unveils SETBP1 as a driver of chromatin rewiring in GATA2 deficiency

Patients with GATA2 deficiency are predisposed to developing myelodysplastic neoplasms (MDS), which can progress to acute myeloid leukemia. This progression is often associated with cytogenetic and somatic alterations. Mutations in SETBP1 and ASXL1 genes are recurrently observed in GATA2 patients, a...

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Authors: Pera, Joan, Romero Moya, Damià, Torralba Sales, Eric, Andersson, Rebecca, García Hernández, Violeta, Magallon Mosella, Maria, Distefano, Maximiliano, Berenguer Balaguer, Clara, Castaño, Julio, Giorgio, Francesca de, Qiu, Zhichao, Iglesias, Arnau, Spurk, Paulina, Montserrat Vazquez, Sara, Pasquali, Lorenzo, Liang, Zhuobin, Català, Albert, Florian, Maria Carolina, Wlodarski, Marcin W., Bigas, Anna, Marin Bejar, Oskar, Giorgetti, Alessandra
Format: article
Status:Published version
Publication Date:2025
Country:España
Institution:Universidad de Oviedo (UNIOVI)
Repository:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/224965
Online Access:https://hdl.handle.net/2445/224965
Access Level:Open access
Keyword:Oncogens
Hematopoesi
Proteïnes supressores de tumors
Oncogenes
Hematopoiesis
Tumor suppressor protein
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spelling Human iPSCs-based modeling unveils SETBP1 as a driver of chromatin rewiring in GATA2 deficiencyPera, JoanRomero Moya, Damià Torralba Sales, EricAndersson, RebeccaGarcía Hernández, VioletaMagallon Mosella, MariaDistefano, MaximilianoBerenguer Balaguer, ClaraCastaño, JulioGiorgio, Francesca deQiu, ZhichaoIglesias, ArnauSpurk, PaulinaMontserrat Vazquez, SaraPasquali, LorenzoLiang, ZhuobinCatalà, AlbertFlorian, Maria CarolinaWlodarski, Marcin W.Bigas, AnnaMarin Bejar, OskarGiorgetti, AlessandraOncogensHematopoesiProteïnes supressores de tumorsOncogenesHematopoiesisTumor suppressor proteinPatients with GATA2 deficiency are predisposed to developing myelodysplastic neoplasms (MDS), which can progress to acute myeloid leukemia. This progression is often associated with cytogenetic and somatic alterations. Mutations in SETBP1 and ASXL1 genes are recurrently observed in GATA2 patients, although their roles remain poorly understood. Here we develop a hiPSC-based system to investigate the impact of SETBP1 and ASXL1 mutations in GATA2 deficiency. Using precise genome editing, we recreate stepwise mutational trajectories observed in GATA2-related MDS. We demonstrate that GATA2 mutation has limited impact on hematopoietic progenitors, while the co-occurrence of SETBP1 or ASXL1 mutations impairs myeloid differentiation. The combination of all three mutations severely depletes myeloid progenitors, recapitulating GATA2-related MDS and highlighting their synergistic interplay. Notably, SETBP1 mutation plays a dominant role in establishing a stable chromatin accessibility landscape, even when co-occurring with ASXL1. Our study establishes an iPSC-based model of GATA2 deficiency, offering new insights into myeloid disease progression and a platform for testing future therapeutic strategies.Springer Science and Business Media LLC2025info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/224965Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))reponame:Dipòsit Digital de la UBinstname:Universidad de Oviedo (UNIOVI)InglésReproducció del document publicat a: https://doi.org/10.1038/s41467-025-65806-9Nature Communications, 2025, vol. 16, 10035https://doi.org/10.1038/s41467-025-65806-9cc-by (c) Pera, Joan et al., 2025https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/2249652026-05-27T06:46:51Z
dc.title.none.fl_str_mv Human iPSCs-based modeling unveils SETBP1 as a driver of chromatin rewiring in GATA2 deficiency
title Human iPSCs-based modeling unveils SETBP1 as a driver of chromatin rewiring in GATA2 deficiency
spellingShingle Human iPSCs-based modeling unveils SETBP1 as a driver of chromatin rewiring in GATA2 deficiency
Pera, Joan
Oncogens
Hematopoesi
Proteïnes supressores de tumors
Oncogenes
Hematopoiesis
Tumor suppressor protein
title_short Human iPSCs-based modeling unveils SETBP1 as a driver of chromatin rewiring in GATA2 deficiency
title_full Human iPSCs-based modeling unveils SETBP1 as a driver of chromatin rewiring in GATA2 deficiency
title_fullStr Human iPSCs-based modeling unveils SETBP1 as a driver of chromatin rewiring in GATA2 deficiency
title_full_unstemmed Human iPSCs-based modeling unveils SETBP1 as a driver of chromatin rewiring in GATA2 deficiency
title_sort Human iPSCs-based modeling unveils SETBP1 as a driver of chromatin rewiring in GATA2 deficiency
dc.creator.none.fl_str_mv Pera, Joan
Romero Moya, Damià
Torralba Sales, Eric
Andersson, Rebecca
García Hernández, Violeta
Magallon Mosella, Maria
Distefano, Maximiliano
Berenguer Balaguer, Clara
Castaño, Julio
Giorgio, Francesca de
Qiu, Zhichao
Iglesias, Arnau
Spurk, Paulina
Montserrat Vazquez, Sara
Pasquali, Lorenzo
Liang, Zhuobin
Català, Albert
Florian, Maria Carolina
Wlodarski, Marcin W.
Bigas, Anna
Marin Bejar, Oskar
Giorgetti, Alessandra
author Pera, Joan
author_facet Pera, Joan
Romero Moya, Damià
Torralba Sales, Eric
Andersson, Rebecca
García Hernández, Violeta
Magallon Mosella, Maria
Distefano, Maximiliano
Berenguer Balaguer, Clara
Castaño, Julio
Giorgio, Francesca de
Qiu, Zhichao
Iglesias, Arnau
Spurk, Paulina
Montserrat Vazquez, Sara
Pasquali, Lorenzo
Liang, Zhuobin
Català, Albert
Florian, Maria Carolina
Wlodarski, Marcin W.
Bigas, Anna
Marin Bejar, Oskar
Giorgetti, Alessandra
author_role author
author2 Romero Moya, Damià
Torralba Sales, Eric
Andersson, Rebecca
García Hernández, Violeta
Magallon Mosella, Maria
Distefano, Maximiliano
Berenguer Balaguer, Clara
Castaño, Julio
Giorgio, Francesca de
Qiu, Zhichao
Iglesias, Arnau
Spurk, Paulina
Montserrat Vazquez, Sara
Pasquali, Lorenzo
Liang, Zhuobin
Català, Albert
Florian, Maria Carolina
Wlodarski, Marcin W.
Bigas, Anna
Marin Bejar, Oskar
Giorgetti, Alessandra
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Oncogens
Hematopoesi
Proteïnes supressores de tumors
Oncogenes
Hematopoiesis
Tumor suppressor protein
topic Oncogens
Hematopoesi
Proteïnes supressores de tumors
Oncogenes
Hematopoiesis
Tumor suppressor protein
description Patients with GATA2 deficiency are predisposed to developing myelodysplastic neoplasms (MDS), which can progress to acute myeloid leukemia. This progression is often associated with cytogenetic and somatic alterations. Mutations in SETBP1 and ASXL1 genes are recurrently observed in GATA2 patients, although their roles remain poorly understood. Here we develop a hiPSC-based system to investigate the impact of SETBP1 and ASXL1 mutations in GATA2 deficiency. Using precise genome editing, we recreate stepwise mutational trajectories observed in GATA2-related MDS. We demonstrate that GATA2 mutation has limited impact on hematopoietic progenitors, while the co-occurrence of SETBP1 or ASXL1 mutations impairs myeloid differentiation. The combination of all three mutations severely depletes myeloid progenitors, recapitulating GATA2-related MDS and highlighting their synergistic interplay. Notably, SETBP1 mutation plays a dominant role in establishing a stable chromatin accessibility landscape, even when co-occurring with ASXL1. Our study establishes an iPSC-based model of GATA2 deficiency, offering new insights into myeloid disease progression and a platform for testing future therapeutic strategies.
publishDate 2025
dc.date.none.fl_str_mv 2025
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/224965
url https://hdl.handle.net/2445/224965
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1038/s41467-025-65806-9
Nature Communications, 2025, vol. 16, 10035
https://doi.org/10.1038/s41467-025-65806-9
dc.rights.none.fl_str_mv cc-by (c) Pera, Joan et al., 2025
https://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by (c) Pera, Joan et al., 2025
https://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Springer Science and Business Media LLC
publisher.none.fl_str_mv Springer Science and Business Media LLC
dc.source.none.fl_str_mv Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
reponame:Dipòsit Digital de la UB
instname:Universidad de Oviedo (UNIOVI)
instname_str Universidad de Oviedo (UNIOVI)
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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