Interleukin-7 receptor α mutational activation can initiate precursor B-cell acute lymphoblastic leukemia
Autor(a) principal: | |
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Data de Publicação: | 2021 |
Outros Autores: | , , , , , , , , , , , , , , , , , , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10451/50691 |
Resumo: | © The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
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Interleukin-7 receptor α mutational activation can initiate precursor B-cell acute lymphoblastic leukemia© The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.Interleukin-7 receptor α (encoded by IL7R) is essential for lymphoid development. Whether acute lymphoblastic leukemia (ALL)-related IL7R gain-of-function mutations can trigger leukemogenesis remains unclear. Here, we demonstrate that lymphoid-restricted mutant IL7R, expressed at physiological levels in conditional knock-in mice, establishes a pre-leukemic stage in which B-cell precursors display self-renewal ability, initiating leukemia resembling PAX5 P80R or Ph-like human B-ALL. Full transformation associates with transcriptional upregulation of oncogenes such as Myc or Bcl2, downregulation of tumor suppressors such as Ikzf1 or Arid2, and major IL-7R signaling upregulation (involving JAK/STAT5 and PI3K/mTOR), required for leukemia cell viability. Accordingly, maximal signaling drives full penetrance and early leukemia onset in homozygous IL7R mutant animals. Notably, we identify 2 transcriptional subgroups in mouse and human Ph-like ALL, and show that dactolisib and sphingosine-kinase inhibitors are potential treatment avenues for IL-7R-related cases. Our model, a resource to explore the pathophysiology and therapeutic vulnerabilities of B-ALL, demonstrates that IL7R can initiate this malignancy.This work was supported by the ERC CoG-648455 consolidator and the ERC PoC-862545 proof-of-concept grants from the European Research Council, under the European Union’s Horizon 2020 research and innovation programme, and the FAPESP/20015/2014 grant from FCT, to J.T.B.; by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) grants 2012/12802-1 and 2014/20015-5 to J.A.Y.; and by an NCI Outstanding Investigator Award R35 R35CA197695 and the American Lebanese Syrian Associated Charities of St Jude Children’s Research Hospital, to C.G.M. A.R.G. is the recipient of an FCT Investigator Grant (CEECIND/02699/2017). A.C. (SFRH/BD/147411/2019), M.B.F. (SFRH/BD/135508/2018), and M.L.O. (SFRH/BD/114102/2015) were recipients of FCT fellowships. M.E. (2016/07724-2, 2017/10653-2), J.R.C. (2017/02400-7) and P.P.Z. (2012/03660-9) were recipients of FAPESP fellowships. J.A.Y. received a productivity fellowship from the National Counsel of Technological and Scientific Development (CNPq 301596/2017-4).Springer NatureRepositório da Universidade de LisboaAlmeida, AfonsoNeto, João LuísCachucho, AnaEuzébio, MayaraMeng, XiangyuKim, RathanaFernandes, MartaRaposo, BeatrizOliveira, Mariana L.Ribeiro, DanielFragoso, RitaZenatti, Priscila P.Soares, TiagoRamos De Matos, MafaldaCorrêa, Juliana RonchiDuque, MafaldaRoberts, Kathryn G.Gu, ZhaohuiQu, ChunxuPereira, ClaraPyne, SusanPyne, Nigel J.Barreto, Vasco M.Bernard-Pierrot, IsabelleClappier, EmannuelleMullighan, Charles G.Grosso, Ana R.Yunes, J. AndrésBarata, João T.2022-01-04T14:44:32Z20212021-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10451/50691engNat Commun. 2021 Dec 14;12(1):726810.1038/s41467-021-27197-52041-1723info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-11-08T16:54:55Zoai:repositorio.ul.pt:10451/50691Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T22:02:02.682720Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Interleukin-7 receptor α mutational activation can initiate precursor B-cell acute lymphoblastic leukemia |
title |
Interleukin-7 receptor α mutational activation can initiate precursor B-cell acute lymphoblastic leukemia |
spellingShingle |
Interleukin-7 receptor α mutational activation can initiate precursor B-cell acute lymphoblastic leukemia Almeida, Afonso |
title_short |
Interleukin-7 receptor α mutational activation can initiate precursor B-cell acute lymphoblastic leukemia |
title_full |
Interleukin-7 receptor α mutational activation can initiate precursor B-cell acute lymphoblastic leukemia |
title_fullStr |
Interleukin-7 receptor α mutational activation can initiate precursor B-cell acute lymphoblastic leukemia |
title_full_unstemmed |
Interleukin-7 receptor α mutational activation can initiate precursor B-cell acute lymphoblastic leukemia |
title_sort |
Interleukin-7 receptor α mutational activation can initiate precursor B-cell acute lymphoblastic leukemia |
author |
Almeida, Afonso |
author_facet |
Almeida, Afonso Neto, João Luís Cachucho, Ana Euzébio, Mayara Meng, Xiangyu Kim, Rathana Fernandes, Marta Raposo, Beatriz Oliveira, Mariana L. Ribeiro, Daniel Fragoso, Rita Zenatti, Priscila P. Soares, Tiago Ramos De Matos, Mafalda Corrêa, Juliana Ronchi Duque, Mafalda Roberts, Kathryn G. Gu, Zhaohui Qu, Chunxu Pereira, Clara Pyne, Susan Pyne, Nigel J. Barreto, Vasco M. Bernard-Pierrot, Isabelle Clappier, Emannuelle Mullighan, Charles G. Grosso, Ana R. Yunes, J. Andrés Barata, João T. |
author_role |
author |
author2 |
Neto, João Luís Cachucho, Ana Euzébio, Mayara Meng, Xiangyu Kim, Rathana Fernandes, Marta Raposo, Beatriz Oliveira, Mariana L. Ribeiro, Daniel Fragoso, Rita Zenatti, Priscila P. Soares, Tiago Ramos De Matos, Mafalda Corrêa, Juliana Ronchi Duque, Mafalda Roberts, Kathryn G. Gu, Zhaohui Qu, Chunxu Pereira, Clara Pyne, Susan Pyne, Nigel J. Barreto, Vasco M. Bernard-Pierrot, Isabelle Clappier, Emannuelle Mullighan, Charles G. Grosso, Ana R. Yunes, J. Andrés Barata, João T. |
author2_role |
author author author author author author author author author author author author author author author author author author author author author author author author author author author author |
dc.contributor.none.fl_str_mv |
Repositório da Universidade de Lisboa |
dc.contributor.author.fl_str_mv |
Almeida, Afonso Neto, João Luís Cachucho, Ana Euzébio, Mayara Meng, Xiangyu Kim, Rathana Fernandes, Marta Raposo, Beatriz Oliveira, Mariana L. Ribeiro, Daniel Fragoso, Rita Zenatti, Priscila P. Soares, Tiago Ramos De Matos, Mafalda Corrêa, Juliana Ronchi Duque, Mafalda Roberts, Kathryn G. Gu, Zhaohui Qu, Chunxu Pereira, Clara Pyne, Susan Pyne, Nigel J. Barreto, Vasco M. Bernard-Pierrot, Isabelle Clappier, Emannuelle Mullighan, Charles G. Grosso, Ana R. Yunes, J. Andrés Barata, João T. |
description |
© The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
publishDate |
2021 |
dc.date.none.fl_str_mv |
2021 2021-01-01T00:00:00Z 2022-01-04T14:44:32Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
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info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10451/50691 |
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http://hdl.handle.net/10451/50691 |
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eng |
language |
eng |
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Nat Commun. 2021 Dec 14;12(1):7268 10.1038/s41467-021-27197-5 2041-1723 |
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openAccess |
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Springer Nature |
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Springer Nature |
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