Publication
Overexpression of wild-type IL-7Rα promotes T-cell acute lymphoblastic leukemia/lymphoma
| Summary: | 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. |
|---|---|
| Main Authors: | Silva, Ana Teresa |
| Other Authors: | Almeida, Afonso R. M.; Cachucho, Ana; Neto, João L.; Demeyer, Sofie; de Matos, Mafalda; Hogan, Thea; Li, Yunlei; Meijerink, Jules; Cools, Jan; Grosso, Ana Rita; Seddon, Benedict; Barata, João T. |
| Subject: | Biochemistry Immunology Hematology Cell Biology SDG 3 - Good Health and Well-being |
| Year: | 2021 |
| Country: | Portugal |
| Document type: | article |
| Access type: | open access |
| Associated institution: | Universidade Nova de Lisboa |
| Language: | English |
| Origin: | Repositório Institucional da UNL |
| _version_ | 1879447185453481984 |
|---|---|
| author | Silva, Ana Teresa |
| author2 | Almeida, Afonso R. M. Cachucho, Ana Neto, João L. Demeyer, Sofie 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 Teresa Almeida, Afonso R. M. Cachucho, Ana Neto, João L. Demeyer, Sofie 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 | DCV - Departamento de Ciências da Vida UCIBIO - Applied Molecular Biosciences Unit American Society of Hematology RUN |
| country_str | PT |
| creators_json_txt | [{\"Person.name\":\"Silva, Ana Teresa\"},{\"Person.name\":\"Almeida, Afonso R. M.\"},{\"Person.name\":\"Cachucho, Ana\"},{\"Person.name\":\"Neto, João L.\"},{\"Person.name\":\"Demeyer, Sofie\"},{\"Person.name\":\"de Matos, Mafalda\"},{\"Person.name\":\"Hogan, Thea\"},{\"Person.name\":\"Li, Yunlei\"},{\"Person.name\":\"Meijerink, Jules\"},{\"Person.name\":\"Cools, Jan\"},{\"Person.name\":\"Grosso, Ana Rita\"},{\"Person.name\":\"Seddon, Benedict\"},{\"Person.name\":\"Barata, João T.\"}] |
| datacite.contributors.contributor.contributorName.fl_str_mv | DCV - Departamento de Ciências da Vida UCIBIO - Applied Molecular Biosciences Unit American Society of Hematology RUN |
| datacite.creators.creator.creatorName.fl_str_mv | Silva, Ana Teresa Almeida, Afonso R. M. Cachucho, Ana Neto, João L. Demeyer, Sofie 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 | 2021-09-23T00:00:00Z |
| datacite.date.available.fl_str_mv | 2021-11-29T23:40:00Z |
| datacite.date.embargoed.fl_str_mv | 2021-11-29T23:40:00Z |
| datacite.rights.fl_str_mv | http://purl.org/coar/access_right/c_abf2 |
| datacite.subjects.subject.fl_str_mv | Biochemistry Immunology Hematology Cell Biology SDG 3 - Good Health and Well-being |
| 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 | DCV - Departamento de Ciências da Vida UCIBIO - Applied Molecular Biosciences Unit American Society of Hematology RUN |
| dc.creator.none.fl_str_mv | Silva, Ana Teresa Almeida, Afonso R. M. Cachucho, Ana Neto, João L. Demeyer, Sofie 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 | 2021-09-23T00:00:00Z |
| dc.date.available.fl_str_mv | 2021-11-29T23:40:00Z |
| dc.date.embargoed.fl_str_mv | 2021-11-29T23:40:00Z |
| dc.format.none.fl_str_mv | application/pdf |
| dc.identifier.none.fl_str_mv | http://hdl.handle.net/10362/128467 |
| dc.language.none.fl_str_mv | eng |
| dc.rights.none.fl_str_mv | http://purl.org/coar/access_right/c_abf2 |
| dc.subject.none.fl_str_mv | Biochemistry Immunology Hematology Cell Biology SDG 3 - Good Health and Well-being |
| 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 | openAccess |
| format | article |
| fulltext.url.fl_str_mv | https://run.unl.pt/bitstreams/fd999c0e-dc26-4c04-88e3-485f9d57bd0a/download |
| funder_facet_str_mv | FCT{{{_:::_}}}Fundação para a Ciência e a Tecnologia |
| funding.funder.alternateName_str_mv | FCT |
| funding.funder.identifier_str_mv | http://doi.org/10.13039/501100001871 |
| funding.funder.name_str_mv | Fundação para a Ciência e a Tecnologia |
| funding.identifier_str_mv | SFRH/BD/18388/2004 |
| funding_str_mv | SFRH/BD/18388/2004 info:eu-repo/grantAgreement/FCT//SFRH%2FBD%2F18388%2F2004/PT |
| id | run_553e01034606a4240e1ec849ac50fa64 |
| identifier.url.fl_str_mv | http://hdl.handle.net/10362/128467 |
| inst_facet_str | urn:organizationAcronym:unl{{{_:::_}}}Universidade Nova de Lisboa |
| instacron_str | unl |
| institution | Universidade Nova de Lisboa |
| instname_str | Universidade Nova de Lisboa |
| language | eng |
| network_acronym_str | run |
| network_name_str | Repositório Institucional da UNL |
| oai_identifier_str | oai:run.unl.pt:10362/128467 |
| organization_str_mv | urn:organizationAcronym:unl |
| person_str_mv | Silva, Ana Teresa Almeida, Afonso R. M. Cachucho, Ana Neto, João L. Demeyer, Sofie de Matos, Mafalda Hogan, Thea Li, Yunlei Meijerink, Jules Cools, Jan Grosso, Ana Rita Seddon, Benedict Barata, João T. |
| publishDate | 2021 |
| repo_facet_str | urn:repositoryAcronym:run{{{_:::_}}}Repositório Institucional da UNL |
| reponame_str | Repositório Institucional da UNL |
| repository_id_str | urn:repositoryAcronym:run |
| service_str_mv | urn:repositoryAcronym:run |
| spelling | engenTight 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/pdfenOverexpression of wild-type IL-7Rα promotes T-cell acute lymphoblastic leukemia/lymphomaSilva, Ana TeresaAlmeida, Afonso R. M.Cachucho, AnaNeto, João L.Demeyer, Sofiede Matos, MafaldaHogan, TheaLi, YunleiMeijerink, JulesCools, JanGrosso, Ana RitaSeddon, BenedictBarata, João T.DCV - Departamento de Ciências da VidaUCIBIO - Applied Molecular Biosciences UnitAmerican Society of HematologyHostingInstitutionOrganizationalRUNe-mailmailto:run@unl.ptrun@unl.ptISSNIsPartOf0006-4971URNIsPartOfPURE: 35107125URNIsPartOfPURE UUID: 4520c49f-3822-4a67-8f99-d57d24cc3a3eURNIsPartOfScopus: 85115322581URNIsPartOfPubMed: 33970999URNIsPartOfPubMedCentral: PMC8462360URNIsPartOfWOS: 000704378100007URNIsPartOfORCID: /0000-0001-6974-4209/work/103949253DOIIsPartOf10.1182/blood.20190005532021-11-29T23:40:00Z2021-09-232021-09-23T00:00:00ZHandlehttp://hdl.handle.net/10362/128467http://purl.org/coar/access_right/c_abf2open accessBiochemistryImmunologyHematologyCell BiologySDG 3 - Good Health and Well-being2641623 bytesFundação 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_abf2application/pdffulltexthttps://run.unl.pt/bitstreams/fd999c0e-dc26-4c04-88e3-485f9d57bd0a/download |
| spellingShingle | Overexpression of wild-type IL-7Rα promotes T-cell acute lymphoblastic leukemia/lymphoma Silva, Ana Teresa Biochemistry Immunology Hematology Cell Biology SDG 3 - Good Health and Well-being |
| status | SINGLETON |
| subject.fl_str_mv | Biochemistry Immunology Hematology Cell Biology SDG 3 - Good Health and Well-being |
| 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 |
| topic | Biochemistry Immunology Hematology Cell Biology SDG 3 - Good Health and Well-being |
| topic_facet | Biochemistry Immunology Hematology Cell Biology SDG 3 - Good Health and Well-being |
| url | http://hdl.handle.net/10362/128467 |
| visible | 1 |