Publicação
Overexpression of wild-type IL-7Rα promotes T-cell acute lymphoblastic leukemia/lymphoma
| Resumo: | Tight regulation of IL-7Rα expression is essential for normal T-cell development. IL-7Rα gain-of-function mutations are known drivers of T-cell acute lymphoblastic leukemia (T-ALL). Although a subset of patients with T-ALL display high IL7R messenger RNA levels and cases with IL7R gains have been reported, the impact of IL-7Rα overexpression, rather than mutational activation, during leukemogenesis remains unclear. In this study, overexpressed IL-7Rα in tetracycline-inducible Il7r transgenic and Rosa26 IL7R knockin mice drove potential thymocyte self-renewal, and thymus hyperplasia related to increased proliferation of T-cell precursors, which subsequently infiltrated lymph nodes, spleen, and bone marrow, ultimately leading to fatal leukemia. The tumors mimicked key features of human T-ALL, including heterogeneity in immunophenotype and genetic subtype between cases, frequent hyperactivation of the PI3K/Akt pathway paralleled by downregulation of p27Kip1 and upregulation of Bcl-2, and gene expression signatures evidencing activation of JAK/STAT, PI3K/Akt/mTOR and Notch signaling. Notably, we also found that established tumors may no longer require high levels of IL-7R expression upon secondary transplantation and progressed in the absence of IL-7, but remain sensitive to inhibitors of IL-7R-mediated signaling ruxolitinib (Jak1), AZD1208 (Pim), dactolisib (PI3K/mTOR), palbociclib (Cdk4/6), and venetoclax (Bcl-2). The relevance of these findings for human disease are highlighted by the fact that samples from patients with T-ALL with high wild-type IL7R expression display a transcriptional signature resembling that of IL-7-stimulated pro-T cells and, critically, of IL7R-mutant cases of T-ALL. Overall, our study demonstrates that high expression of IL-7Rα can promote T-cell tumorigenesis, even in the absence of IL-7Rα mutational activation. |
|---|---|
| Autores principais: | Silva, Ana |
| Outros Autores: | Almeida, Afonso; Cachucho, Ana; Neto, João Luís; Demeyer, Sofie; Ramos De Matos, Mafalda; Hogan, Thea; Li, Yunlei; Meijerink, Jules; Cools, Jan; Grosso, Ana Rita; Seddon, Benedict; Barata, João T. |
| Ano: | 2021 |
| País: | Portugal |
| Tipo de documento: | artigo |
| Tipo de acesso: | acesso restrito |
| Instituição associada: | Universidade de Lisboa |
| Idioma: | inglês |
| Origem: | Repositório da Universidade de Lisboa |
| _version_ | 1877771162387218432 |
|---|---|
| author | Silva, Ana |
| author2 | Almeida, Afonso Cachucho, Ana Neto, João Luís Demeyer, Sofie Ramos De Matos, Mafalda Hogan, Thea Li, Yunlei Meijerink, Jules Cools, Jan Grosso, Ana Rita Seddon, Benedict Barata, João T. |
| author2_role | author author author author author author author author author author author author |
| author_facet | Silva, Ana Almeida, Afonso Cachucho, Ana Neto, João Luís Demeyer, Sofie Ramos De Matos, Mafalda Hogan, Thea Li, Yunlei Meijerink, Jules Cools, Jan Grosso, Ana Rita Seddon, Benedict Barata, João T. |
| author_role | author |
| contributor_name_str_mv | Repositório Científico de Acesso Aberto da ULisboa |
| country_str | PT |
| creators_json_txt | [{\"Person.name\":\"Silva, Ana\"},{\"Person.name\":\"Almeida, Afonso\",\"Person.identifier.cienciaID\":\"081E-39B1-1041\",\"Person.identifier.orcid\":\"0000-0002-4292-8558\",\"Person.identifier.scopusAuthorID\":\"7202913704\"},{\"Person.name\":\"Cachucho, Ana\",\"Person.identifier.cienciaID\":\"D013-F1F4-DB01\",\"Person.identifier.orcid\":\"0000-0003-4815-1687\"},{\"Person.name\":\"Neto, João Luís\",\"Person.identifier.cienciaID\":\"E512-57B7-6129\",\"Person.identifier.orcid\":\"0000-0003-0863-158X\"},{\"Person.name\":\"Demeyer, Sofie\"},{\"Person.name\":\"Ramos De Matos, Mafalda\",\"Person.identifier.orcid\":\"0000-0002-4206-2854\"},{\"Person.name\":\"Hogan, Thea\"},{\"Person.name\":\"Li, Yunlei\"},{\"Person.name\":\"Meijerink, Jules\"},{\"Person.name\":\"Cools, Jan\"},{\"Person.name\":\"Grosso, Ana Rita\",\"Person.identifier.cienciaID\":\"3D18-571E-133A\",\"Person.identifier.orcid\":\"0000-0001-6974-4209\",\"Person.identifier.scopusAuthorID\":\"26639262500\"},{\"Person.name\":\"Seddon, Benedict\"},{\"Person.name\":\"Barata, João T.\",\"Person.identifier.orcid\":\"0000-0002-4826-8976\",\"Person.identifier.researcherID\":\"D-9181-2015\",\"Person.identifier.scopusAuthorID\":\"7006937224\"}] |
| datacite.contributors.contributor.contributorName.fl_str_mv | Repositório Científico de Acesso Aberto da ULisboa |
| datacite.creators.creator.creatorName.fl_str_mv | Silva, Ana Almeida, Afonso Cachucho, Ana Neto, João Luís Demeyer, Sofie Ramos De Matos, Mafalda Hogan, Thea Li, Yunlei Meijerink, Jules Cools, Jan Grosso, Ana Rita Seddon, Benedict Barata, João T. |
| datacite.date.Accepted.fl_str_mv | 2021-01-01T00:00:00Z |
| datacite.date.available.fl_str_mv | 2021-09-28T13:03:19Z |
| datacite.date.embargoed.fl_str_mv | 2021-09-28T13:03:19Z |
| datacite.rights.fl_str_mv | http://purl.org/coar/access_right/c_16ec |
| datacite.titles.title.fl_str_mv | Overexpression of wild-type IL-7Rα promotes T-cell acute lymphoblastic leukemia/lymphoma |
| dc.contributor.none.fl_str_mv | Repositório Científico de Acesso Aberto da ULisboa |
| dc.creator.none.fl_str_mv | Silva, Ana Almeida, Afonso Cachucho, Ana Neto, João Luís Demeyer, Sofie Ramos De Matos, Mafalda Hogan, Thea Li, Yunlei Meijerink, Jules Cools, Jan Grosso, Ana Rita Seddon, Benedict Barata, João T. |
| dc.date.Accepted.fl_str_mv | 2021-01-01T00:00:00Z |
| dc.date.available.fl_str_mv | 2021-09-28T13:03:19Z |
| dc.date.embargoed.fl_str_mv | 2021-09-28T13:03:19Z |
| dc.format.none.fl_str_mv | application/pdf |
| dc.identifier.none.fl_str_mv | http://hdl.handle.net/10451/49655 |
| dc.language.none.fl_str_mv | eng |
| dc.publisher.none.fl_str_mv | ASH Publications |
| dc.rights.none.fl_str_mv | http://purl.org/coar/access_right/c_16ec |
| dc.title.fl_str_mv | Overexpression of wild-type IL-7Rα promotes T-cell acute lymphoblastic leukemia/lymphoma |
| dc.type.none.fl_str_mv | http://purl.org/coar/resource_type/c_6501 |
| description | Tight regulation of IL-7Rα expression is essential for normal T-cell development. IL-7Rα gain-of-function mutations are known drivers of T-cell acute lymphoblastic leukemia (T-ALL). Although a subset of patients with T-ALL display high IL7R messenger RNA levels and cases with IL7R gains have been reported, the impact of IL-7Rα overexpression, rather than mutational activation, during leukemogenesis remains unclear. In this study, overexpressed IL-7Rα in tetracycline-inducible Il7r transgenic and Rosa26 IL7R knockin mice drove potential thymocyte self-renewal, and thymus hyperplasia related to increased proliferation of T-cell precursors, which subsequently infiltrated lymph nodes, spleen, and bone marrow, ultimately leading to fatal leukemia. The tumors mimicked key features of human T-ALL, including heterogeneity in immunophenotype and genetic subtype between cases, frequent hyperactivation of the PI3K/Akt pathway paralleled by downregulation of p27Kip1 and upregulation of Bcl-2, and gene expression signatures evidencing activation of JAK/STAT, PI3K/Akt/mTOR and Notch signaling. Notably, we also found that established tumors may no longer require high levels of IL-7R expression upon secondary transplantation and progressed in the absence of IL-7, but remain sensitive to inhibitors of IL-7R-mediated signaling ruxolitinib (Jak1), AZD1208 (Pim), dactolisib (PI3K/mTOR), palbociclib (Cdk4/6), and venetoclax (Bcl-2). The relevance of these findings for human disease are highlighted by the fact that samples from patients with T-ALL with high wild-type IL7R expression display a transcriptional signature resembling that of IL-7-stimulated pro-T cells and, critically, of IL7R-mutant cases of T-ALL. Overall, our study demonstrates that high expression of IL-7Rα can promote T-cell tumorigenesis, even in the absence of IL-7Rα mutational activation. |
| dirty | 0 |
| eu_rights_str_mv | restrictedAccess |
| format | article |
| fulltext.url.fl_str_mv | https://repositorio.ulisboa.pt/bitstreams/7011e4bd-b9ea-419d-8197-78d4cad24331/download |
| funder_facet_str_mv | EC{{{_:::_}}}European Commission FCT{{{_:::_}}}Fundação para a Ciência e a Tecnologia |
| funding.funder.alternateName_str_mv | EC FCT |
| funding.funder.identifier_str_mv | http://doi.org/10.13039/501100008530 http://doi.org/10.13039/501100001871 |
| funding.funder.name_str_mv | European Commission Fundação para a Ciência e a Tecnologia |
| funding.identifier_str_mv | 648455 SFRH/BD/18388/2004 |
| funding.name_str_mv | H2020 |
| funding_str_mv | 648455 info:eu-repo/grantAgreement/EC/H2020/648455/EU SFRH/BD/18388/2004 info:eu-repo/grantAgreement/FCT//SFRH%2FBD%2F18388%2F2004/PT |
| id | ul_3c0626389fe014b22da935a4f90607d5 |
| identifier.url.fl_str_mv | http://hdl.handle.net/10451/49655 |
| inst_facet_str | urn:organizationAcronym:ul{{{_:::_}}}Universidade de Lisboa |
| instacron_str | ul |
| institution | Universidade de Lisboa |
| instname_str | Universidade de Lisboa |
| language | eng |
| network_acronym_str | ul |
| network_name_str | Repositório da Universidade de Lisboa |
| oai_identifier_str | oai:repositorio.ulisboa.pt:10451/49655 |
| organization_str_mv | urn:organizationAcronym:ul |
| person_str_mv | Silva, Ana Almeida, Afonso Almeida, Afonso https://www.ciencia-id.pt/081E-39B1-1041 081E-39B1-1041 http://orcid.org/0000-0002-4292-8558 0000-0002-4292-8558 Cachucho, Ana Cachucho, Ana https://www.ciencia-id.pt/D013-F1F4-DB01 D013-F1F4-DB01 http://orcid.org/0000-0003-4815-1687 0000-0003-4815-1687 Neto, João Luís Neto, João Luís https://www.ciencia-id.pt/E512-57B7-6129 E512-57B7-6129 http://orcid.org/0000-0003-0863-158X 0000-0003-0863-158X Demeyer, Sofie Ramos De Matos, Mafalda Ramos De Matos, Mafalda http://orcid.org/0000-0002-4206-2854 0000-0002-4206-2854 Hogan, Thea Li, Yunlei Meijerink, Jules Cools, Jan Grosso, Ana Rita Grosso, Ana Rita https://www.ciencia-id.pt/3D18-571E-133A 3D18-571E-133A http://orcid.org/0000-0001-6974-4209 0000-0001-6974-4209 Seddon, Benedict Barata, João T. Barata, João T. http://orcid.org/0000-0002-4826-8976 0000-0002-4826-8976 |
| publishDate | 2021 |
| publisher.none.fl_str_mv | ASH Publications |
| repo_facet_str | urn:repositoryAcronym:ul{{{_:::_}}}Repositório da Universidade de Lisboa |
| reponame_str | Repositório da Universidade de Lisboa |
| repository_id_str | urn:repositoryAcronym:ul |
| service_str_mv | urn:repositoryAcronym:ul |
| spelling | engASH Publicationspt_PTTight regulation of IL-7Rα expression is essential for normal T-cell development. IL-7Rα gain-of-function mutations are known drivers of T-cell acute lymphoblastic leukemia (T-ALL). Although a subset of patients with T-ALL display high IL7R messenger RNA levels and cases with IL7R gains have been reported, the impact of IL-7Rα overexpression, rather than mutational activation, during leukemogenesis remains unclear. In this study, overexpressed IL-7Rα in tetracycline-inducible Il7r transgenic and Rosa26 IL7R knockin mice drove potential thymocyte self-renewal, and thymus hyperplasia related to increased proliferation of T-cell precursors, which subsequently infiltrated lymph nodes, spleen, and bone marrow, ultimately leading to fatal leukemia. The tumors mimicked key features of human T-ALL, including heterogeneity in immunophenotype and genetic subtype between cases, frequent hyperactivation of the PI3K/Akt pathway paralleled by downregulation of p27Kip1 and upregulation of Bcl-2, and gene expression signatures evidencing activation of JAK/STAT, PI3K/Akt/mTOR and Notch signaling. Notably, we also found that established tumors may no longer require high levels of IL-7R expression upon secondary transplantation and progressed in the absence of IL-7, but remain sensitive to inhibitors of IL-7R-mediated signaling ruxolitinib (Jak1), AZD1208 (Pim), dactolisib (PI3K/mTOR), palbociclib (Cdk4/6), and venetoclax (Bcl-2). The relevance of these findings for human disease are highlighted by the fact that samples from patients with T-ALL with high wild-type IL7R expression display a transcriptional signature resembling that of IL-7-stimulated pro-T cells and, critically, of IL7R-mutant cases of T-ALL. Overall, our study demonstrates that high expression of IL-7Rα can promote T-cell tumorigenesis, even in the absence of IL-7Rα mutational activation.application/pdfpt_PTOverexpression of wild-type IL-7Rα promotes T-cell acute lymphoblastic leukemia/lymphomaSilva, AnaPersonalAlmeida, AfonsoDSpacehttp://dspace.org/items/d127aa83-8977-4df5-91da-c11465d31384DSpacehttp://dspace.org/items/d127aa83-8977-4df5-91da-c11465d31384AlmeidaAfonsoCiência IDhttps://www.ciencia-id.pt081E-39B1-1041ORCIDhttp://orcid.org0000-0002-4292-8558Scopus Author IDhttps://www.scopus.com7202913704PersonalCachucho, AnaDSpacehttp://dspace.org/items/661d12ae-121a-4ca1-a8a0-599de0fd8571DSpacehttp://dspace.org/items/661d12ae-121a-4ca1-a8a0-599de0fd8571Cebola CachuchoAna PatríciaCiência IDhttps://www.ciencia-id.ptD013-F1F4-DB01ORCIDhttp://orcid.org0000-0003-4815-1687PersonalNeto, João LuísDSpacehttp://dspace.org/items/beb96947-3a83-40b9-965a-8c76b8eac953DSpacehttp://dspace.org/items/beb96947-3a83-40b9-965a-8c76b8eac953Aguiar Martins NetoJoão LuísCiência IDhttps://www.ciencia-id.ptE512-57B7-6129ORCIDhttp://orcid.org0000-0003-0863-158XDemeyer, SofiePersonalRamos De Matos, MafaldaDSpacehttp://dspace.org/items/712894e0-c03d-4290-b28a-730c933694f1DSpacehttp://dspace.org/items/712894e0-c03d-4290-b28a-730c933694f1Ramos de MatosMafaldaORCIDhttp://orcid.org0000-0002-4206-2854Hogan, TheaLi, YunleiMeijerink, JulesCools, JanPersonalGrosso, Ana RitaDSpacehttp://dspace.org/items/607e3b4e-024c-4fae-83fe-e0ed9c3f66a8DSpacehttp://dspace.org/items/607e3b4e-024c-4fae-83fe-e0ed9c3f66a8GrossoAna RitaCiência IDhttps://www.ciencia-id.pt3D18-571E-133AORCIDhttp://orcid.org0000-0001-6974-4209Scopus Author IDhttps://www.scopus.com26639262500Seddon, BenedictPersonalBarata, João T.DSpacehttp://dspace.org/items/06f27f7f-1c6c-4c03-a70d-52f8a388bd3bDSpacehttp://dspace.org/items/06f27f7f-1c6c-4c03-a70d-52f8a388bd3bBarataJoãoORCIDhttp://orcid.org0000-0002-4826-8976Researcher IDhttps://www.researcherid.comD-9181-2015Scopus Author IDhttps://www.scopus.com7006937224HostingInstitutionOrganizationalRepositório Científico de Acesso Aberto da ULisboae-mailmailto:repositorio@ulisboa.ptrepositorio@ulisboa.ptISSNIsPartOf1528-0020DOIIsPartOf10.1182/blood.20190005532021-09-28T13:03:19Z20212021-01-01T00:00:00ZHandlehttp://hdl.handle.net/10451/49655http://purl.org/coar/access_right/c_16ecrestricted access2641466 bytesEuropean CommissionIL-7/IL-7R signaling networks in health and malignancyinfo:eu-repo/grantAgreement/EC/H2020/648455/EU648455H2020Crossref Funder IDhttp://doi.org/10.13039/501100008530Fundação para a Ciência e a TecnologiaIL-7- AND PI3K-MEDIATED SIGNALING IN T-CELL LEUKEMIA: THE ROLE OF EXTERNAL AND CELL-AUTONOMOUS SIGNALS IN TUMORIGENESISinfo:eu-repo/grantAgreement/FCT//SFRH%2FBD%2F18388%2F2004/PTSFRH/BD/18388/2004Crossref Funder IDhttp://doi.org/10.13039/501100001871literaturehttp://purl.org/coar/resource_type/c_6501journal articlehttp://purl.org/coar/access_right/c_16ecapplication/pdffulltexthttps://repositorio.ulisboa.pt/bitstreams/7011e4bd-b9ea-419d-8197-78d4cad24331/downloadBlood1381210401052 |
| spellingShingle | Overexpression of wild-type IL-7Rα promotes T-cell acute lymphoblastic leukemia/lymphoma Silva, Ana |
| status | SINGLETON |
| title | Overexpression of wild-type IL-7Rα promotes T-cell acute lymphoblastic leukemia/lymphoma |
| title_full | Overexpression of wild-type IL-7Rα promotes T-cell acute lymphoblastic leukemia/lymphoma |
| title_fullStr | Overexpression of wild-type IL-7Rα promotes T-cell acute lymphoblastic leukemia/lymphoma |
| title_full_unstemmed | Overexpression of wild-type IL-7Rα promotes T-cell acute lymphoblastic leukemia/lymphoma |
| title_short | Overexpression of wild-type IL-7Rα promotes T-cell acute lymphoblastic leukemia/lymphoma |
| title_sort | Overexpression of wild-type IL-7Rα promotes T-cell acute lymphoblastic leukemia/lymphoma |
| url | http://hdl.handle.net/10451/49655 |
| visible | 1 |