Myeloid leukemia vulnerabilities embedded in long noncoding RNA locus MYNRL15
Summary: The noncoding genome presents a largely untapped source of new biological insights, including thousands of long noncoding RNA (lncRNA) loci. While lncRNA dysregulation has been reported in myeloid malignancies, their functional relevance remains to be systematically interrogated. We perform...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-10-01
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| Series: | iScience |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004223019211 |
| _version_ | 1827781729938571264 |
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| author | Michelle Ng Lonneke Verboon Hasan Issa Raj Bhayadia Marit Willemijn Vermunt Robert Winkler Leah Schüler Oriol Alejo Konstantin Schuschel Eniko Regenyi Dorit Borchert Michael Heuser Dirk Reinhardt Marie-Laure Yaspo Dirk Heckl Jan-Henning Klusmann |
| author_facet | Michelle Ng Lonneke Verboon Hasan Issa Raj Bhayadia Marit Willemijn Vermunt Robert Winkler Leah Schüler Oriol Alejo Konstantin Schuschel Eniko Regenyi Dorit Borchert Michael Heuser Dirk Reinhardt Marie-Laure Yaspo Dirk Heckl Jan-Henning Klusmann |
| author_sort | Michelle Ng |
| collection | DOAJ |
| description | Summary: The noncoding genome presents a largely untapped source of new biological insights, including thousands of long noncoding RNA (lncRNA) loci. While lncRNA dysregulation has been reported in myeloid malignancies, their functional relevance remains to be systematically interrogated. We performed CRISPRi screens of lncRNA signatures from normal and malignant hematopoietic cells and identified MYNRL15 as a myeloid leukemia dependency. Functional dissection suggests an RNA-independent mechanism mediated by two regulatory elements embedded in the locus. Genetic perturbation of these elements triggered a long-range chromatin interaction and downregulation of leukemia dependency genes near the gained interaction sites, as well as overall suppression of cancer dependency pathways. Thus, this study describes a new noncoding myeloid leukemia vulnerability and mechanistic concept for myeloid leukemia. Importantly, MYNRL15 perturbation caused strong and selective impairment of leukemia cells of various genetic backgrounds over normal hematopoietic stem and progenitor cells in vitro, and depletion of patient-derived xenografts in vivo. |
| first_indexed | 2024-03-11T15:22:55Z |
| format | Article |
| id | doaj.art-2ac8f8d3abed48ac804f570792af8c42 |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-03-11T15:22:55Z |
| publishDate | 2023-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-2ac8f8d3abed48ac804f570792af8c422023-10-28T05:08:43ZengElsevieriScience2589-00422023-10-012610107844Myeloid leukemia vulnerabilities embedded in long noncoding RNA locus MYNRL15Michelle Ng0Lonneke Verboon1Hasan Issa2Raj Bhayadia3Marit Willemijn Vermunt4Robert Winkler5Leah Schüler6Oriol Alejo7Konstantin Schuschel8Eniko Regenyi9Dorit Borchert10Michael Heuser11Dirk Reinhardt12Marie-Laure Yaspo13Dirk Heckl14Jan-Henning Klusmann15Department of Pediatric Hematology and Oncology, Martin Luther University Halle-Wittenberg, 06120 Halle (Saale), GermanyDepartment of Pediatrics, Goethe University Frankfurt, 60323 Frankfurt (Main), Germany; Frankfurt Cancer Institute, Goethe University Frankfurt, 60323 Frankfurt (Main), Germany; German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz and German Cancer Research Center (DKFZ), Heidelberg, GermanyDepartment of Pediatrics, Goethe University Frankfurt, 60323 Frankfurt (Main), Germany; Frankfurt Cancer Institute, Goethe University Frankfurt, 60323 Frankfurt (Main), Germany; German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz and German Cancer Research Center (DKFZ), Heidelberg, GermanyDepartment of Pediatrics, Goethe University Frankfurt, 60323 Frankfurt (Main), Germany; Frankfurt Cancer Institute, Goethe University Frankfurt, 60323 Frankfurt (Main), Germany; German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz and German Cancer Research Center (DKFZ), Heidelberg, GermanyDepartment of Pediatrics, Goethe University Frankfurt, 60323 Frankfurt (Main), Germany; German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz and German Cancer Research Center (DKFZ), Heidelberg, GermanyDepartment of Pediatrics, Goethe University Frankfurt, 60323 Frankfurt (Main), Germany; Frankfurt Cancer Institute, Goethe University Frankfurt, 60323 Frankfurt (Main), Germany; German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz and German Cancer Research Center (DKFZ), Heidelberg, GermanyDepartment of Pediatrics, Goethe University Frankfurt, 60323 Frankfurt (Main), Germany; Frankfurt Cancer Institute, Goethe University Frankfurt, 60323 Frankfurt (Main), Germany; German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz and German Cancer Research Center (DKFZ), Heidelberg, GermanyDepartment of Pediatric Hematology and Oncology, Martin Luther University Halle-Wittenberg, 06120 Halle (Saale), GermanyDepartment of Pediatrics, Goethe University Frankfurt, 60323 Frankfurt (Main), Germany; Frankfurt Cancer Institute, Goethe University Frankfurt, 60323 Frankfurt (Main), Germany; German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz and German Cancer Research Center (DKFZ), Heidelberg, GermanyDepartment of Pediatric Hematology and Oncology, Martin Luther University Halle-Wittenberg, 06120 Halle (Saale), Germany; Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, 14195 Berlin, GermanyDepartment of Pediatric Hematology and Oncology, Hannover Medical School, 30625 Hannover, GermanyDepartment of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, 30625 Hannover, GermanyClinic for Pediatrics III, University Hospital Essen, 45147 Essen, GermanyDepartment of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, 14195 Berlin, GermanyInstitute for Experimental Pediatric Hematology and Oncology, Goethe University Frankfurt, 60323 Frankfurt (Main), Germany; Corresponding authorDepartment of Pediatrics, Goethe University Frankfurt, 60323 Frankfurt (Main), Germany; Frankfurt Cancer Institute, Goethe University Frankfurt, 60323 Frankfurt (Main), Germany; German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz and German Cancer Research Center (DKFZ), Heidelberg, Germany; Corresponding authorSummary: The noncoding genome presents a largely untapped source of new biological insights, including thousands of long noncoding RNA (lncRNA) loci. While lncRNA dysregulation has been reported in myeloid malignancies, their functional relevance remains to be systematically interrogated. We performed CRISPRi screens of lncRNA signatures from normal and malignant hematopoietic cells and identified MYNRL15 as a myeloid leukemia dependency. Functional dissection suggests an RNA-independent mechanism mediated by two regulatory elements embedded in the locus. Genetic perturbation of these elements triggered a long-range chromatin interaction and downregulation of leukemia dependency genes near the gained interaction sites, as well as overall suppression of cancer dependency pathways. Thus, this study describes a new noncoding myeloid leukemia vulnerability and mechanistic concept for myeloid leukemia. Importantly, MYNRL15 perturbation caused strong and selective impairment of leukemia cells of various genetic backgrounds over normal hematopoietic stem and progenitor cells in vitro, and depletion of patient-derived xenografts in vivo.http://www.sciencedirect.com/science/article/pii/S2589004223019211BiochemistryCancer |
| spellingShingle | Michelle Ng Lonneke Verboon Hasan Issa Raj Bhayadia Marit Willemijn Vermunt Robert Winkler Leah Schüler Oriol Alejo Konstantin Schuschel Eniko Regenyi Dorit Borchert Michael Heuser Dirk Reinhardt Marie-Laure Yaspo Dirk Heckl Jan-Henning Klusmann Myeloid leukemia vulnerabilities embedded in long noncoding RNA locus MYNRL15 iScience Biochemistry Cancer |
| title | Myeloid leukemia vulnerabilities embedded in long noncoding RNA locus MYNRL15 |
| title_full | Myeloid leukemia vulnerabilities embedded in long noncoding RNA locus MYNRL15 |
| title_fullStr | Myeloid leukemia vulnerabilities embedded in long noncoding RNA locus MYNRL15 |
| title_full_unstemmed | Myeloid leukemia vulnerabilities embedded in long noncoding RNA locus MYNRL15 |
| title_short | Myeloid leukemia vulnerabilities embedded in long noncoding RNA locus MYNRL15 |
| title_sort | myeloid leukemia vulnerabilities embedded in long noncoding rna locus mynrl15 |
| topic | Biochemistry Cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2589004223019211 |
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