X‐linked inhibitor of apoptosis protein represents a promising therapeutic target for relapsed/refractory ALL
Abstract Acute lymphoblastic leukemia (ALL) represents the most frequent malignancy in children, and relapse/refractory (r/r) disease is difficult to treat, both in children and adults. In search for novel treatment options against r/r ALL, we studied inhibitor of apoptosis proteins (IAP) and Smac m...
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| Format: | Article |
| Language: | English |
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Springer Nature
2022-11-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.202114557 |
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| author | Michela Carlet Karin Schmelz Jenny Vergalli Tobias Herold Daniela Senft Vindi Jurinovic Thomas Hoffmann Jutta Proba Nina Weichert Christian Junghanß Mareike Roth Georg Eschenburg Malwine Barz Günter Henze Cornelia Eckert Angelika Eggert Johannes Zuber Patrick Hundsdoerfer Irmela Jeremias |
| author_facet | Michela Carlet Karin Schmelz Jenny Vergalli Tobias Herold Daniela Senft Vindi Jurinovic Thomas Hoffmann Jutta Proba Nina Weichert Christian Junghanß Mareike Roth Georg Eschenburg Malwine Barz Günter Henze Cornelia Eckert Angelika Eggert Johannes Zuber Patrick Hundsdoerfer Irmela Jeremias |
| author_sort | Michela Carlet |
| collection | DOAJ |
| description | Abstract Acute lymphoblastic leukemia (ALL) represents the most frequent malignancy in children, and relapse/refractory (r/r) disease is difficult to treat, both in children and adults. In search for novel treatment options against r/r ALL, we studied inhibitor of apoptosis proteins (IAP) and Smac mimetics (SM). SM‐sensitized r/r ALL cells towards conventional chemotherapy, even upon resistance against SM alone. The combination of SM and chemotherapy‐induced cell death via caspases and PARP, but independent from cIAP‐1/2, RIPK1, TNFα or NF‐κB. Instead, XIAP was identified to mediate SM effects. Molecular manipulation of XIAP in vivo using microRNA‐30 flanked shRNA expression in cell lines and patient‐derived xenograft (PDX) models of r/r ALL mimicked SM effects and intermediate XIAP knockdown‐sensitized r/r ALL cells towards chemotherapy‐induced apoptosis. Interestingly, upon strong XIAP knockdown, PDX r/r ALL cells were outcompeted in vivo, even in the absence of chemotherapy. Our results indicate a yet unknown essential function of XIAP in r/r ALL and reveal XIAP as a promising therapeutic target for r/r ALL. |
| format | Article |
| id | doaj-art-b9528d06f61749f38311ce38d1fa6f9a |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2022-11-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-b9528d06f61749f38311ce38d1fa6f9a2025-08-24T11:43:31ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842022-11-0115111710.15252/emmm.202114557X‐linked inhibitor of apoptosis protein represents a promising therapeutic target for relapsed/refractory ALLMichela Carlet0Karin Schmelz1Jenny Vergalli2Tobias Herold3Daniela Senft4Vindi Jurinovic5Thomas Hoffmann6Jutta Proba7Nina Weichert8Christian Junghanß9Mareike Roth10Georg Eschenburg11Malwine Barz12Günter Henze13Cornelia Eckert14Angelika Eggert15Johannes Zuber16Patrick Hundsdoerfer17Irmela Jeremias18Research Unit Apoptosis in Hematopoietic Stem Cells, Helmholtz Zentrum München, German Center for Environmental Health (HMGU)Department of Pediatric Oncology/Hematology, Charité‐UniversitätsmedizinResearch Unit Apoptosis in Hematopoietic Stem Cells, Helmholtz Zentrum München, German Center for Environmental Health (HMGU)Research Unit Apoptosis in Hematopoietic Stem Cells, Helmholtz Zentrum München, German Center for Environmental Health (HMGU)Research Unit Apoptosis in Hematopoietic Stem Cells, Helmholtz Zentrum München, German Center for Environmental Health (HMGU)Research Unit Apoptosis in Hematopoietic Stem Cells, Helmholtz Zentrum München, German Center for Environmental Health (HMGU)Research Institute of Molecular Pathology (IMP)Department of Pediatric Oncology/Hematology, Charité‐UniversitätsmedizinDepartment of Pediatric Oncology/Hematology, Charité‐UniversitätsmedizinDepartment of Medicine, Clinic III – Hematology, Oncology, Palliative Medicine, Rostock University Medical CenterResearch Institute of Molecular Pathology (IMP)Department of Pediatric Surgery, University Medical Center Hamburg‐EppendorfUniversity Children's Hospital ZurichDepartment of Pediatric Oncology/Hematology, Charité‐UniversitätsmedizinDepartment of Pediatric Oncology/Hematology, Charité‐UniversitätsmedizinDepartment of Pediatric Oncology/Hematology, Charité‐UniversitätsmedizinResearch Institute of Molecular Pathology (IMP)Department of Pediatric Oncology/Hematology, Charité‐UniversitätsmedizinResearch Unit Apoptosis in Hematopoietic Stem Cells, Helmholtz Zentrum München, German Center for Environmental Health (HMGU)Abstract Acute lymphoblastic leukemia (ALL) represents the most frequent malignancy in children, and relapse/refractory (r/r) disease is difficult to treat, both in children and adults. In search for novel treatment options against r/r ALL, we studied inhibitor of apoptosis proteins (IAP) and Smac mimetics (SM). SM‐sensitized r/r ALL cells towards conventional chemotherapy, even upon resistance against SM alone. The combination of SM and chemotherapy‐induced cell death via caspases and PARP, but independent from cIAP‐1/2, RIPK1, TNFα or NF‐κB. Instead, XIAP was identified to mediate SM effects. Molecular manipulation of XIAP in vivo using microRNA‐30 flanked shRNA expression in cell lines and patient‐derived xenograft (PDX) models of r/r ALL mimicked SM effects and intermediate XIAP knockdown‐sensitized r/r ALL cells towards chemotherapy‐induced apoptosis. Interestingly, upon strong XIAP knockdown, PDX r/r ALL cells were outcompeted in vivo, even in the absence of chemotherapy. Our results indicate a yet unknown essential function of XIAP in r/r ALL and reveal XIAP as a promising therapeutic target for r/r ALL.https://doi.org/10.15252/emmm.202114557PDXrelapsed/refractory acute lymphoblastic leukemiasmac mimeticstherapeutic targetXIAP |
| spellingShingle | Michela Carlet Karin Schmelz Jenny Vergalli Tobias Herold Daniela Senft Vindi Jurinovic Thomas Hoffmann Jutta Proba Nina Weichert Christian Junghanß Mareike Roth Georg Eschenburg Malwine Barz Günter Henze Cornelia Eckert Angelika Eggert Johannes Zuber Patrick Hundsdoerfer Irmela Jeremias X‐linked inhibitor of apoptosis protein represents a promising therapeutic target for relapsed/refractory ALL EMBO Molecular Medicine PDX relapsed/refractory acute lymphoblastic leukemia smac mimetics therapeutic target XIAP |
| title | X‐linked inhibitor of apoptosis protein represents a promising therapeutic target for relapsed/refractory ALL |
| title_full | X‐linked inhibitor of apoptosis protein represents a promising therapeutic target for relapsed/refractory ALL |
| title_fullStr | X‐linked inhibitor of apoptosis protein represents a promising therapeutic target for relapsed/refractory ALL |
| title_full_unstemmed | X‐linked inhibitor of apoptosis protein represents a promising therapeutic target for relapsed/refractory ALL |
| title_short | X‐linked inhibitor of apoptosis protein represents a promising therapeutic target for relapsed/refractory ALL |
| title_sort | x linked inhibitor of apoptosis protein represents a promising therapeutic target for relapsed refractory all |
| topic | PDX relapsed/refractory acute lymphoblastic leukemia smac mimetics therapeutic target XIAP |
| url | https://doi.org/10.15252/emmm.202114557 |
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